Nitrogen-containing tricyclic compounds and drugs containing the same

ABSTRACT

A phenothiazine, acridan, acridone oxime, acridone hydrazone and dibenzodiazepine derivative represented by formula (I)  
                 
 
     effective against diseases in which histamine, leukotrienes, etc. participate and effective in preventing or treating diseases in which chemical mediators such as histamine and leukotrienes participate, for example, asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy and food allergy.

[0001] This application is the national phase under 35 U.S.C. §371 ofprior PCT International Application No. PCT/JP97/00789 which has anInternational filing date of Mar. 13, 1997 which designated the UnitedStates of America, the entire contents of which are hereby incorporatedby reference.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field

[0003] The present invention relates to a nitrogen-containing tricycliccompound useful as a medicine, a medicine containing the same andprocesses for producing the same. More particularly, it relates to anovel nitrogen-containing tricyclic compound useful as a medicine fordiseases against which the effect of inhibiting the binding of IgEreceptor γ to a tyrosine kinase of 72 kDa is efficacious.

[0004] 2. Prior Art

[0005] The bronchial asthma and the atopic diseases in human beingsappear in consequence of highly intriacate vital reactions. It issuspected that most of these conditions are caused because variouschemical mediators liberated from mast cells and basophils, as triggeredby antigen-antibody reactions, induce vital disturbances as bycontracting such smooth muscles as bronchial muscles and vessels of thepulmonary circulation or enhancing permeability of blood vessels.

[0006] As the chemical mediators liberated from mast cells andbasophils, histamine, leukotrienes, prostaglandins, TNF, etc. have beenknown. It is well known that histamine, among other substances mentionedabove, is the most significant chemical mediator for the allergicrhinitis and the urticaria in human beings. The leucotrienes compriseleucotrienes B₄, C₄, and D₄ and the relation thereof with the asthmaticconvulsion has been attracting attention.

[0007] Heretofore, the development of medicines for the prevention,alleviation, or elimination of the crisis of symptoms of allergicdiseases has been aimed at repressing the creation and liberation ofsuch chemical mediators or antagonizing the effects thereof.

[0008] Sodium cromoglycate (Intal™) having been marketed since 1969 is atypical example of these drugs.

[0009] However, the conventional antiallergic agents typified by Intal™show difference in the chemical mediator liberation inhibitoryconcentration between in vitro and in vivo. Moreover, sensitivities tothese drugs widely vary from patient to patient and their actionmechanisms still remain unknown in many points.

[0010] Mast cells and basophils closely relating to allergic diseaseshave a highly affinitive receptor, Fcε RI, for the IgE antibody on thecell membrane thereof. IgE antibody's binding to this receptor forms across-linkage with the corresponding polyvalent antigen, theintracellular signal transmission mechanism is activated. Then histamineis liberated or leukotrienes and prostaglandins are formed andliberated, thus inducing the onset of the so-called allergic symptoms.It is furthermore considered that the cytokines such as TNF andinterleukins thus produced interact with other cells and thus make thediseases chronic.

[0011] Under these circumstances, the present inventors have paid theirattention to the activation of a non-receptor type tyrosine kinaselocated at the early stage in the activation of the intracellular signaltransmission mechanism upon liberation of chemical mediators from mastcells or basophils. It is known that this tyrosine kinase is activatedwhen it binds to the phosphorylated tyrosine activation motif (TAM)region in the IgE receptor γ chain. By inhibiting this binding tothereby inhibit the activation of the tyrosine kinase of 72 kDa, theactivation of the intracellular signal transmission mechanism dependingon the IgE antibody in mast cells or basophils can be inhibited. As aresult, also the liberation of the above chemical mediators can beinhibited. The present inventors have found out that desired objects canbe achieved by using nitrogen-containing tricyclic compounds representedby the following formula (I), thus completing the present invention.

DISCLOSURE OF THE INVENTION

[0012] An object of the present invention is to provide a novel acridonederivative and a pharmacologically acceptable salt thereof which isefficacious in preventing or treating asthma, allergic rhinitis, atopicdermatitis, urticaria, hay fever, gastrointestinal allergy, foodallergy, etc. Another object of the present invention is to provide amedicine containing as the active ingredient the compound, a hydratethereof or a pharmacologically acceptable salt thereof.

[0013] Accordingly, the present invention relates to anitrogen-containing tricyclic compound represented by the followingformula (I), a hydrate thereof or a pharmacologically acceptable saltthereof:

[0014] {wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same ordifferent from each other and each represents hydrogen, hydroxy, cyano,nitro, optionally substituted carbamoyl, halogeno, optionallyhalogenated lower alkyl, optionally substituted cycloalkyl, optionallyhalogenated lower alkoxy, acyl, optionally protected carboxy, optionallysubstituted aryl, optionally substituted heteroaryl, cycloalkylalkyl,hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, cyanoalkyl, acylalkyl, optionally substitutedcarbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl,alkoxyalkenyl, optionally protected carboxyalkenyl, optionallysubstituted arylalkenyl, optionally substituted heteroarylalkenyl,cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl,optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl,optionally protected carboxyalkynyl, optionally substituted arylalkynyl,optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl,optionally substituted carbamoylalkynyl, hydroxyalkoxy, alkoxyalkoxy,optionally protected carboxyalkoxy, optionally substituted arylalkoxy,optionally substituted heteroarylalkoxy, —A—NR⁹R¹⁰ [wherein A representsoptionally substituted alkylene, optionally substituted alkenylene,optionally substituted alkynylene or a single bond; and R⁹ and R¹⁰ arethe same or different from each other and each represents hydrogen,optionally halogenated lower alkyl, optionally substituted aryl or acyl,or R⁹ and R¹⁰ may form together with the nitrogen atom to which they arebonded a ring optionally having additional nitrogen, oxygen or sulfur],or

[0015] [wherein B represents optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkynylene or a singlebond; R¹¹ represents optionally halogenated lower alkyl or aminooptionally substituted by lower alkyl; and x represents an integer offrom 0 to 2];

[0016] provided that two of R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ adjacentto each other may form together with the carbon atom to which they arebonded a ring optionally containing oxygen, sulfur or nitrogen andoptionally substituted;

[0017] Z represents

[0018] [wherein y represents an integer of from 0 to 2],

[0019] [wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are the same ordifferent from each other and each represents hydrogen, optionallysubstituted carbamoyl, optionally halogenated lower alkyl, optionallysubstituted cycloalkyl, acyl, optionally halogenated loweralkylsulfonyl, optionally substituted arylsulfonyl, optionally protectedcarboxy, optionally substituted aryl, optionally substituted heteroaryl,cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protectedcarboxyalkyl, optionally substituted arylalkyl,optionallysubstitutedheteroarylalkyl, cyanoalkyl, acylalkyl, optionallysubstituted carbamoylalkyl, optionally halogenated alkenyl,hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl,optionally substituted arylalkenyl, optionally substitutedheteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substitutedcarbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl,alkoxyalkynyl, optionally protected carboxyalkynyl, optionallysubstituted arylalkynyl, optionally substituted heteroarylalkynyl,cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl,—W—NR¹⁸R¹⁹ (wherein W represents optionally branched alkylene,optionally branched alkenylene, optionally branched alkynylene or asingle bond; R¹⁸ and R¹⁹ are the same or different from each other andeach represents hydrogen, optionally halogenated lower alkyl or acyl, orR¹⁸ and R¹⁹ may form together with the nitrogen atom to which they arebonded a ring optionally containing additional nitrogen, oxygen orsulfur)];

[0020] D represents optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkynylene or

[0021] (wherein m and 1 are each an integer of from 0 to 6; the ring Ameans an optionally substituted hydrocarbon ring or an optionallysubstituted heterocycle); and

[0022] Q represents optionally substituted carbamoyl, acyl, acylalkyl,optionally protected carboxy, optionally substituted heteroaryl, or—NR²⁰R²¹ [wherein R²⁰ and R²¹ are the same or different from each otherand each represents hydrogen, optionally halogenated lower alkyl,optionally halogenated lower alkoxy, hydroxylated alkyl, alkoxyalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted aryloxy, optionally substitutedarylalkoxy, optionally substituted heteroaryloxy, optionally substitutedheteroarylalkoxy, optionally protected carboxyalkyl, acyl, optionallysubstituted acylalkyl, optionally substituted acylamino, optionallysubstituted acylaminoalkyl, cyanoalkyl, optionally substitutedcarbamoylalkyl, optionally substituted aminoalkyl, cyanoalkyl,acylalkyl, cycloalkyl, cycloalkylalkyl or amidino optionally substitutedby lower alkyl, or R²⁰ and R²¹ may form together with the nitrogen atomto which they are bonded an optionally substituted 3- to 8-membered ringwhich may have, as its ring-member other than carbon, at least onemember selected from the group consisting of nitrogen, sulfur, oxygenand —NR²² (wherein R²²represents hydrogen, optionally halogenated loweralkyl, acyl, optionally substituted acylalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl or—S(O)_(s)—(Y)_(u)—R²³ (wherein R²³ represents hydrogen, optionallyhalogenated lower alkyl or optionally substituted aryl; Y representsmethylene; s is an integer of from 0 to 2; and u is 0 or 1))];

[0023] provided that the following cases are excluded:

[0024] (1) the one where R⁵ and R⁶ are both hydrogen atoms;

[0025] (2) the one where Z is

[0026] [wherein y is an integer of from 0 to 2]; R⁵ is fluoro; and R⁶ isfluoro or trifluoromethyl; and

[0027] (3) the one where Z is

[0028] [wherein y is an integer of from 0 to 2]; R⁵ is carboxy; and R⁶is chloro}.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The term “halogen atom” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and R⁸ in the formula (I) means fluorine, chlorine,bromine, iodine, etc.

[0030] The term “lower alkyl” in “optionally halogenated lower alkyl” asused in the definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²² and R²³ meanslinear or branched C₁₋₆ alkyl, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,2-ethylpropyl, n-hexyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl,1,3-dimethylbutyl, 1-ethyl-2-methylpropyl and 1-methyl-2-ethylpropylgroups.

[0031] In such a case, the term “optionally halogenated” means that theabove alkyl may be substituted by 1 to 3 halogen atoms such as fluorine,chlorine, bromine or iodine. Namely, the “optionally halogenated loweralkyl” as used in the formula (I) includes trifluoromethyl, dibromoethyland the like.

[0032] The term “lower alkenyl” in “optionally halogenated loweralkenyl” as used in the definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ R²⁰ and R²¹ means linear orbranched C₁₋₆ alkenyl, for example, vinyl, 1-propenyl, 2-propenyl,isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl,2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl and3-butenyl groups. The lower alkenyl as used herein further includes theabove-mentioned alkenyl substituted by 1 to 3 halogen atoms.

[0033] The term “lower alkynyl” in “optionally halogenated loweralkynyl” as used in the definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰ and R²¹ means linear orbranched C₁₋₆ alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl and2-methyl-3-propynyl groups. The lower alkynyl as used herein furtherincludes the above-mentioned alkynyl substituted by 1 to 3 halogenatoms.

[0034] The term “cycloalkyl” in “optionally substituted cycloalkyl” asused in the definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰ and R²¹ means C₃₋₈ ones such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl groups.

[0035] The term “cycloalkylalkyl” as used in the definition of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷ and R⁸ means those wherein the above lower alkyl isattached to any carbon atom of the above cycloalkyl.

[0036] The term “lower alkoxy” in “optionally halogenated lower alkoxy”as used in the definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R²⁰ and R²¹means linear or branched C₁₋₆ alkoxy, for example, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy,1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, 2,2-dimethylpropyloxy,2-ethylpropyloxy, n-hexyloxy, 1,2-dimethylbutyloxy,2,3-dimethylbutyloxy, 1,3-dimethylbutyloxy, 1-ethyl-2-methylpropyloxyand 1-methyl-2-ethylpropyloxy groups.

[0037] In such a case, the term “optionally halogenated” means that theabove alkoxy may be substituted by 1 to 3 halogen atoms such asfluorine, chlorine, bromine or iodine. Namely, the “optionallyhalogenated lower alkoxy” as used herein includes trifluoromethoxy,dibromoethoxy and the like.

[0038] The term “acyl” as used in the definition of R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²² and Q means those derived from saturated aliphaticmonocarboxylic acids such as acetyl, propionyl, butyryl, valeryl,isovaleryl and pivaloyl groups, those derived from unsaturated aliphaticcarboxylic acids such as acryloyl, propioloyl, methacryloyl, crotonoyland isocrotonoyl groups, those derived from carbocyclic carboxylic acidssuch as benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl andcinnamoyl groups, those derived from heterocyclic carboxylic acids suchas furoyl, thenoyl, nicotinoyl and isonicotinoyl groups, those derivedfrom hydroxy carboxylic acids or alkoxy carboxylic acids such asglycoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl, salicyloyl, anisoyl,vaniloyl, piperonyloyl and galloyl groups and those derived from variousamino acids.

[0039] The term “acylalkyl” as used in the definition of R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²² andQ means those wherein the above acyl is attached to any carbon atom ofthe above lower alkyl. Examples thereof include acetylmethyl,propionylmethyl, benzoylethyl, naphthoylpropyl, cinnamoylpropyl,salicyloylbutyl, nicotinoylpentyl and glyceroylhexyl groups, though,needless to say, the present invention is not restricted thereto.

[0040] The term “acylalkenyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶and R¹⁷ means thosewherein the acyl is attached to any carbon atom of the above alkenyl.Examples thereof include benzoyl-1-ethylenyl and3-nicotinoyl-2-propylenyl, though, needless to say, the presentinvention is not restricted thereto.

[0041] The term “acylalkynyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ means thosewherein the acyl is attached to any carbon atom of the above loweralkynyl.

[0042] The term “hydroxylated alkyl” as used in the definition of R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰ and R²¹means those wherein 1 to 3 hydroxyl groups are attached to any carbonatom of the above lower alkyl, for example, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,3-hydroxypropyl, 2,3-dihydroxypropyl and 3,4-dihydroxybutyl groups.

[0043] The term “hydroxyalkenyl” as used in the definition of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ meansthose wherein hydroxy is attached to any carbon atom of the above loweralkenyl.

[0044] The term “hydroxyalkynyl” as used in the definition of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ meansthose wherein hydroxy is attached to any carbon atom of the above loweralkynyl.

[0045] The term “alkoxyalkyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰ and R²¹means those wherein the above lower alkoxy is attached to any carbonatom of the above lower alkyl, for example, methoxymethyl, ethoxymethyl,ethoxyethyl and 2-ethoxypropyl groups, though the present invention isnot restricted thereto.

[0046] The term “alkoxyalkenyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ means thosewherein the above lower alkoxy is attached to any carbon atom of theabove lower alkenyl, for example, methoxyethylenyl and ethoxypropylenylgroups, though the present invention is not restricted thereto.

[0047] The term “alkoxyalkynyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ means thosewherein the above lower alkoxy is attached to any carbon atom of theabove lower alkynyl.

[0048] The term “cyanoalkyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²² and R²³means those wherein cyano is attached to any carbon atom of the abovelower alkyl, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl,1-cyanopropyl and 2-cyanopropyl groups.

[0049] The term “cyanoalkenyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ means those whereincyano is attached to any carbon atom of the above lower alkenyl.

[0050] The term “cyanoalkynyl” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ means those whereincyano is attached to any carbon atom of the above lower alkynyl.

[0051] The term “hydroxyalkoxy” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and R⁸ means those wherein hydroxy is attached to anycarbon atom of the above lower alkoxy, for example, hydroxymethoxy,1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy, 2-hydoxypropoxy and3-hydroxypropoxy groups.

[0052] The term “alkoxyalkoxy” as used in the definition of R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and R⁸ means those wherein the above lower alkoxy isattached to any carbon atom of the above lower alkoxy, for example,methoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy, ethoxymethoxy,1-ethoxyethoxy, 2-ethoxyethoxy, 1-methoxypropoxy and 2-methoxypropoxygroups.

[0053] The term “aryl” in “optionally substituted aryl” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R9, R¹⁰, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²² and R²³ means, for example, phenyl,1-naphthyl, 2-naphthyl and anthracenyl groups.

[0054] The term “aryl” in “optionally substituted arylalkyl” as used inthe definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R²⁰, R²¹ and R²² has the same meaning as the one definedabove. In such a case, the term “alkyl” has the same meaning as that of“lower alkyl” defined above.

[0055] The term “optionally substituted heteroaryl” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R²⁰, R²¹, R²² and Q means those derived from single or fused ringscontaining 1 to 4 heteroatoms of at least one type selected from thegroup consisting of sulfur, oxygen and nitrogen atoms. Examples thereofinclude pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, benzimidazolyl,indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl,isoquinolyl, cinnolin, phthalazyl, quinoxalyl, naphthyridyl, quinazolyland imidazopyridyl groups.

[0056] The term “optionally substituted heteroarylalkyl” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R²⁰, R²¹ and R²² means those wherein the above heteroaryl isattached to any carbon atom of the above lower alkyl.

[0057] The term “optionally substituted heteroarylalkenyl” as used inthe definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶ and R¹⁷ means those wherein the above heteroaryl is attached to anycarbon atom of the above lower alkenyl.

[0058] The term “optionally substituted heteroarylalkynyl” as used inthe definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶ and R¹⁷ means those wherein the above heteroaryl is attached to anycarbon atom of the above lower alkynyl.

[0059] The term “optionally substituted carbamoyl” as used in thedefinition of R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷ and Q means carbamoyl optionally having 1 or 2 substituents on thenitrogen atom.

[0060] The terms “optionally substituted carbamoylalkyl,carbamoylalkenyl and carbamoyalalkynyl” as used in the definition of R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰ and R²¹mean those wherein optionally substituted carbamoyl is attached to anycarbon atom of the above lower alkyl, alkenyl and alkynyl.

[0061] Examples of the substituents in the optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted arylalkenyl, optionallysubstituted heteroarylalkenyl, optionally substituted arylalkynyl,optionally substituted heteroarylalkynyl, optionally substitutedarylalkoxy, optionally substituted heteroarylalkoxy, optionallysubstituted carbamoyl, optionally substituted carbamoylalkyl, optionallysubstituted carbamoylalkenyl and optionally substituted carbamoylalkynylinclude hydroxy; lower alkyl such as methyl, ethyl, n-propyl andisopropyl; lower alkoxy such as methoxy, ethoxy, n-propoxy andisopropoxy; halogen atom such as fluorine, chlorine, bromine and iodine;cyano; acyl such as acetyl, propionyl and benzoyl; amino; nitro:optionally protected carboxyl; carbamoyl; acylamino; sulfamoyl;alkylsulfonylamino; arylsulfonylamino; heteroaryl; carboxyalkyl;carboxyalkoxy; heteroarylalkyl; heteroarylalkoxy; methylenedioxy; andethylenedioxy. The substituents are selected therefrom.

[0062] Examples of the protective groups in the “optionally protectedcarboxy” as used in the definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹ and Q include lower alkylsuch as methyl, ethyl and tert-butyl; lower alkyl substituted byoptionally substituted phenyl such as p-methoxybenzyl, p-nitrobenyl,3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenatedlower alkyl such as 2,2,2-trichloroethyl and 2-iodoethyl; loweralkanoyloxy-substitutedloweralkyl suchaspivaloyloxymethyl,acetoxymethyl, propionyloxymethyl, butyryloxymethyl, varelyloxymethyl,1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and2-pivaloyloxyethyl; higher alkanoyloxy-substitutedloweralkylsuchaspalmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl;lower alkoxycarbonyloxy-substituted lower alkyl such asmethoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and1-(isopropoxycarbonyloxy)ethyl; carboxy-substituted lower alkyl such ascarboxymethyl and 2-carboxyethyl; benzoyloxy-substituted lower alkyloptionally substituted by heteroaryl such as 3-phthalidyl,4-glycyloxybenzoyloxymethyl, etc.; (substituted dioxolene)-substitutedlower alkyl such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl;cycloalkyl-substituted lower alkanoyloxy-substituted lower alkyl such as1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy-substitutedlower alkyl such as 1-cyclohexyloxycarbonyloxyethyl. Moreover, variousacid amides are also usable therefor. In summary, the carboxy-protectivegroup may be an arbitrary one, so long as it is decomposed by some meansto give a carboxylic acid in vivo.

[0063] The term “optionally protected carboxylalkyl” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R²⁰ and R²¹ means those wherein carboxy optionally having the aboveprotective group(s) is attached to any carbon atom of the above loweralkyl.

[0064] The term “optionally protected carboxylalkoxy” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R²⁰ and R²¹ means those wherein optionally protected carboxy isattached to any carbon atom of the above lower alkoxy. In such a case,the protective group has the same meaning as the one defined above.

[0065] The term “optionally protected carboxyalkenyl” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶and R¹⁷ means those wherein optionally protected carboxy is attached toany carbon atom of the above lower alkenyl. In such a case, theprotective group has the same meaning as the one defined above.

[0066] The term “optionally protected carboxyalkynyl” as used in thedefinition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶and R¹⁷ means those wherein optionally protected carboxy is attached toany carbon atom of the above lower alkynyl. In such a case, theprotective group has the same meaning as the one defined above.

[0067] Examples of the ring in “R²⁰ and R²¹ may form together with thenitrogen atom to which they are bonded a ring” of the formula —NR²⁰R²¹as used in the definition of Q include aziridine, azetidine,pyrrolidine, piperidine, perhydroazepine, perhydroazocine, piperazine,homopiperazine, morpholine, thiomorpholine, thiomorpholine dioxide,indoline, isoindoline, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, 2,3-dihdyrobenzoxazine,2,3-dihydrobenzothiazine, pyrrole, imidazole, pyrazole, triazole,tetrazole, indole, isoindole, indazole and benzotriazole.

[0068] (a) The term “alkylene” as used in the definition of A, B and Wmeans methylene, ethylene, trimethylene, tetramethylene, pentamethyleneor hexamethylene.

[0069] (b) The term “alkenylene” as used in the definition of A, B and Wmeans ethenylene, propenylene, butenylene, pentenylene, hexenylene,butanedienylene, pentanedienylene, hexanedienylene or hexanetrienylene.

[0070] (c) The term “alkynylene” as used in the definition of A, B and Wmeans ethynylene, propynylene, butynylene, pentynylene, hexynylene,butanediynylene, pentanediynylene, hexanediynylene or hexanetriynylene.

[0071] (d) The term “hydrocarbon ring” as used in the definition of thering A means cyclopropane, cyclobutane, cyclopentane, cyclohexane,benzene, naphthalene, etc.

[0072] (e) The term “heterocycle” as used in the definition of the ringA means pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,homopiperazine, pyrrole, pyrazole, imidazole, triazole, tetrazole,oxazole, thiazole, thiadiazole, pyridine, pyridazine, pyrimidine,pyrazine, indole, imidazopyridine, quinoline, naphthyridine,phthalazine, etc.

[0073] In the case of the compounds of the present invention havingasymmetric carbon atoms, it is needless to say that the optical isomersthereof are also included in the scope of the present invention.Furthermore, hydrates thereof are included in the scope of the presentinvention.

[0074] Examples of the pharmacologically acceptable salts as used in thepresent invention include inorganic acid salts such as hydrochlorides,hydrobromides, sulfates and phosphates; organic acid salts such asacetates, maleates, tartrates, methanesulfonates, benzenesulfonates andtoluenesulfonates; and salts of amino acids such as aspartic andglutamic acids.

[0075] To facilitate the understanding of the present invention, and notby way of limitation, typical examples of the compounds of the presentinvention will be given. Each compound is expressed in a free state:

[0076] 1)1,2-dimethyl-10-[3-[(2-hydroxy-3-methylphenyl)methylamino]propyl]phenothiazine-5-dioxide

[0077] 2)1,2-dimethyl-10-[3-[(3-chloro-2-hydroxyphenyl)methylamino]propyl]phenothiazine-5-dioxide

[0078] 3)1,2-dimethyl-10-[3-[(5-methoxy-2-furanyl)methylamino]propyl]phenothiazine-5-dioxide

[0079] 4)1,2-dimethyl-10-[3-[(3-methoxy-2-thienyl)methylamino]propyl]phenothiazine-5-dioxide

[0080] 5)1,2-dimethyl-10-[3-(4-hydroxy-4-phenylpiperidinyl)propyl]phenothiazine-5-dioxide

[0081] 6)1,2-dimethyl-10-[3-(4-benzylpiperazinyl)propyl]phenothiazine-5-dioxide

[0082] 7)1,2-dimethyl-10-[3-[N-[(2-hydroxyphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide

[0083] 8)1,2-dimethyl-10-[3-[N-[(2-hydroxy-3-methylphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide

[0084] 9)(E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(2-carboxyethyl)ether

[0085] 10)(E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(1-carboxyethyl)ether.

MODE FOR CARRYING OUT THE INVENTION

[0086] The compounds of the present invention can be produced bycombining generally known methods. Now, main processes generally usablefor producing the compounds of the present invention will beillustrated.

[0087] Production Processs 1

[0088] Compounds of the formula (I) wherein Z is —S(O)_(y)— and Q is—NR²⁰R²¹ can be produced by the following process.

[0089] i) A phenothiazine derivative represented by the formula (II)synthesized by a publicly known method [for example, those described inJ. Org. Chem., 20,1577 (1955).; ibid., 35, 4254 (1970).; J. Chem. Soc.,(C) 2437 (1970).; and Chem. Ind., 238 (1966).] is reacted in thepresence of a base with a compound represented by the formula (III)having leaving groups at both ends to thereby give a phenothiazinederivative represented by the formula (IV). Preferable examples of thebase usable herein include sodium hydride, n-butyllithium andt-butoxypotassium. Preferable examples of the leaving groups includehalogeno and sulfonate. Any reaction solvent may be used therefor, solong as it remains inert during the reaction. Next, the leaving group L′in the compound (IV) is substituted by phthalimide. The resultingphthalimide compound represented by the formula (V) is then treated withhydrazine hydrate to give an amine compound represented by the generalformula (VI). Next, this amine compound (VI) is condensed underdehydration with an aldehyde compound (VII: wherein R represents alkyl,alkenyl, alkynyl, aryl or heteroaryl). The Schiff base thus obtained isthen treated with a reducing agent such as sodium borohydride to give analkylamine compound represented by the formula (VIII). Any reactionsolvent may be used therefor, so long as it remains inert during thereaction.

[0090] Alternatively, the phthalimide compound (V) serving as anintermediate may be synthesized in the following manner. Namely, thecompound (II) is reacted with a compound having a leaving group L at oneend and a protected hydroxyl group at another end to give a compoundrepresented by the formula (IV′). Subsequently, the compound (IV′)isdeblocked in a conventional manner to give an alcohol (IV″), which isthen reacted with phthalimide under the conditions of the Mitsunobureaction to give a phthalimide compound.

[0091] ii) The compound (IV) is treated with a primary or secondaryamine, or the compound (VI) is treated with a compound having a leavinggroup L (IX and/or X′) to give a compound represented by the formula(X).

[0092] iii) A sulfoxide compound (XI) and a sulfonyl compound (XII) canbe produced by oxidizing the sulfur atoms in the compounds (VIII) and(IX) or oxidizing the sulfur atom in the stage of the intermediate (IV)or (VI) in the process of the above i) or ii) followed by appropriatereactions.

[0093] Production Process 2

[0094] Compounds of the formula (I) wherein Z is —C(═NOR¹²)— or—C(═NNR¹³R¹⁴) and Q is —NR²⁰R²¹ can be produced by the followingprocess.

[0095] An acridone compound (XIII) synthesized by a publicly knownmethod (for example, the one described in JP-A 7-3161359) is reactedwith a compound (III) to give a compound (XIV). Next, this compound(XIV) is reacted with potassium phthalimide to give a compound (XV).Then the compound (XV) is reacted with oxalyl chloride. The acridiniumsalt thus obtained is reacted with a hydroxylamine derivative (R¹²ONH₂:wherein R¹² is as defined above) or a hydrazine derivative (R¹³R¹⁴NNH₂:wherein R¹³ and R¹⁴ are each as defined above) to give a compoundrepresented by the formula (XVI) or (XVI′). Then the obtained compoundis reacted with hydrazine hydrate to give a primary amine compoundrepresented by the formula (XVII) or (XVII′). Further, secondary ortertiary amines can be produced in accordance with the methods of i) ofii) in the above production process 1. Production Process 3

[0096] Compounds represented by the formula (I) wherein Z is—C(═CR¹⁶R¹⁷)— and Q is —NR²⁰R²¹ can be produced by the followingprocess.

[0097] The compound represented by the formula (XIV) given in theproduction process 2 is reacted with a metal compound M—CHR¹⁶R¹⁷(wherein M means a metal and R¹⁶ and R¹⁷ are each as defined above suchas alkyl lithium, etc.) to give an acridan compound represented by theformula (XVIII). Next, this product is treated in the same manner as theone described in the production process 1 ii) to give an amine compoundrepresented by the formula (IX).

[0098] Production Process 4

[0099] Compounds represented by the formula (I) wherein Z is—C(═O)N(R¹⁵)— or —N(R¹⁵C(═O)— and Q is —NR²⁰R²¹ can be produced by thefollowing process.

[0100] The procedure of the step i) or ii) in the production process 1was repeated while replacing the phenothiazine derivative represented bythe formula (II) employed In the production process 1 by adibenzodiazepine derivative (XX or XX′) produced by a publicly knownmethod [Indian J. Chem., 23B, 85 (1984).] or Production Example 13 or14. Thus a compound represented by the formula (XXI or XXI′) can beobtained.

[0101] Production Process 5

[0102] Compounds of the formula (I) wherein Q is heteroaryl can beproduced by the following process.

[0103] The compound represented by the formula (XXII) obtained by theproduction processes 1, 2, 3 and 4 and having a leaving group L′ istreated with magnesium to give a Grignard reagent. Next, this Grignardreagent is reacted with an optionally substituted heteroaryl halidederived from, e.g., pyridine or pyrimidine in the presence of1,3-bis(diphenylphosphino)propane nickel dichloride [Ni (dppp) Cl₂] togive a compound represented by the formula (XXIV).

[0104] Production Process 6

[0105] Compounds of the formula (I) wherein Q is optionally substitutedcarbamoyl, acyl or optionally protected carboxy can be produced by thefollowing process.

[0106] The compound represented by the formula (XXII) obtained by theproduction processes 1, 2, 3 and 4 and having a leaving group L′ istreated with a reagent for cyanation such as sodium cyanide in thepresence of a base to give a nitrile compound (XXV), which is thenhydrolyzed to give an unsubstituted carbamoyl compound (XXVI) or anester or carboxylic acid represented by the formula (XXVII). Asubstituted carbamoyl compound (XXVIII) can be obtained by alkylating oraralkylating the unsubstituted carbamoyl compound (XXVI) or reacting theester or a reactive derivative (acid halide, reactive ester, etc.)derived from the carboxylic acid in a conventional manner with a primaryor a secondary amine. A protected carboxyl compound can be obtained byreacting the reactive derivative derived from the carboxylic acid withan alcohol derivative.

[0107] To illustrate the usefulness of the present invention,pharmacological experimental examples will be given.

PHARMACOLOGICAL EXPERIMENTAL EXAMPLES

[0108] (1) Inhibitory Effects on Various Mediators Release from RatBasophilic Leukemia Cell Line (RBL-2H3)

[0109] i) Experimental Method

[0110] IgE-sensitized RBL-2H3 cells (i.e., a cell line originating inrat cells) release and produce not only histamine and serotonin but alsocytokines such as TNF α and prostaglandins which are inflammatorymediators after stimulation with IgE sepecific antibody. In thisexperimental system, inhibitory effects on various mediators releasewere examined by using serotonin as an indication.

[0111] The cells were beforehand labeled with [³H]-labeled serotoninand, at the same time, sensitized with the IgE antibody. Afterincubating with the compounds of the present invention, the cells werestimulated with the specific antigen. Then the inhibitory activity ofeach compound was calculated from the amount of the [³H]-labeledserotonin thus liberated into the medium and the amount of [³H]-labeledserotonin liberated when no compound of the present invention was added.

[0112] ii) Results of the experiment

[0113] The results are shown in Tables 1 to 3. TABLE 1 Inhibitoryeffects on various mediators release from rat basophilic leukemia cellline (RBL-2H3) IC₅₀ (μM) in serotonin liberation from Ex. no. RBL-2H3cells 1 5 3 10 6 10 7 8 8 0.1 9 1> 10 3 22 0.1 23 2 24 3 25 3 26 2 27 328 0.8 29 0.8 30 2 31 0.5 32 0.5 33 1 34 2 35 1 36 1 37 2 38 8 39 2 40 541 5 42 2 43 4 44 1 45 1 46 0.5 47 0.5 48 0.3 49 2 50 2 51 2 52 3 53 0.854 1 55 8 56 3 57 2 58 2 59 3 60 6 61 6 62 3 63 3 64 3 65 0.5 66 0.5 671 68 4 69 1 70 2 71 8 72 8 73 2 74 2 75 6 76 3 5 5 78 4 79 2 80 1 81 182 2 83 2 84 2 85 3 86 1 87 3 88 1

[0114] TABLE 2 IC₅₀ (μM) in serotonin liberation from Ex. no. RBL-2H3cells 89 2 90 3 91 5 93 3 94 <1 95 3 98 0.5 99 5 100 2 101 5 102 1 103<3 104 <3 105 2 106 2 107 2 108 2 109 3 110 1 111 2 112 1 113 3 114 2115 3 116 10 117 2 118 10 119 6 120 3 121 1 122 3 123 3 124 2 125 2 1263 127 2 128 1 129 <1 130 3 131 3 132 2 133 1 134 3 135 2 136 0.8 137 1138 3 139 2 140 3 141 0.5 143 3 144 8 145 6 146 3 147 3 148 8 149 8 1501 151 2 152 1 153 6 154 6 155 4 156 3 157 1 158 3 159 5 160 2 161 0.8162 1 163 3 164 2 165 0.3 166 0.5

[0115] TABLE 3 IC₅₀ (μM) in serotonin liberation from Ex. no. RBL-2H3cells 168 2 169 0.5 170 0.5 171 0.8 172 3 173 0.3 174 0.5 175 0.8 176 2177 1 179 2 180 2 181 2 182 2 183 3 184 0.5 185 0.5 186 10 188 1 189 0.8190 0.5 191 3 192 5 193 2 194 10 195 0.5 196 5 197 8 199 10 200 0.4 20110 202 6 206 15 207 15 208 3 209 15 210 10 211 10 212 6 215 3 216 3 2172 220 6 222 10 223 10 230 6 231 3 232 10 234 <3 235 <1 236 1 237 10 23912 240 5 241 4 242 6 243 6 244 3 247 10 248 10 249 10 251 5 253 10 25412 255 8 257 12 258 6 259 4 260 6 261 10 262 8

[0116] The compound numbers correspond to Example Nos. as will be givenhereinafter (the same will apply hereinafter).

[0117] (2) Inhibitory Effects on Various Mediators Release from Human

[0118] i) Experimental method

[0119] 6 ml of 6% dextran (for separating leukocytes, having a highmolecular weight) was added to 20 ml of heparinized blood. Afterstirring well, the resulting mixture was allowed to stand at 37° C. for30 min and thus erythrocytes were precipitated. The upper layer wastaken up and phosphate buffered saline (D-PBS) was added theretofollowed by centrifugation at 185 g for 8 minutes to give a crudeleukocyte fraction. These cells were subjected to hypotonic hematolysisand then suspended in D-PBS(+) containing 0.1%-BSA. The resultingsuspension was used in the subsequent experiment as the leukocytefraction containing basophils. 0.4 ml of this cell suspension waspreliminarily heated to 37° C. for 5 min and then 0.05 ml of a specimensolution was added thereto followed by a pretreatment at 37° C. for 15min. Next, 0.05 ml of a mite antigen solution was added thereto toinduce an antigen-antibody reaction. After 10 min, the reaction wasceased by ice-cooling. Then the reaction mixture was centrifuged at 185g for 10 min and histamine and peptide leukotrienes in the resultingsupernatant were determined by using enzyme immunoassay kits. From theresults of the assay, the activities of the acridone derivatives ofinhibiting the liberation of histamine and peptide leukotriene weredetermined.

[0120] ii) Results of the Experiment

[0121] The results are given in Tables 4 to 7 wherein the term“leukotriene” means peptide leukotriene. TABLE 4 Inhibitory effects onvarious mediators release from human basophils IC₅₀ (μM) in mediatorliberation from human basophils Ex. no. histamine leukotriene 22 10-3010 23 10-30 10-30 24 10-30 10-30 25 30 10-30 26 <10 <10 27  30-100 10-3028 10-30 3 29 10-30  3-10 30  3-10 <3 32  30-100 10-30 33 10-30 10 34 3-10 3 35 3  3-10 36  3-10  3-10 37 10-30  3-10 39 10-30 10-30 42  3-10<3 44 10-30 10 45  3-10 3 46 10-30 10-30 47  3-10 3 48  3-10 3 49 10 3-10 50 30 10-30 51 10-30 10-30 53  30-100 10-30 54 10  3-10 58 10-3010-30

[0122] TABLE 5 IC₅₀ (μM) in mediator liberation from human basophils Ex.no. histamine leukotriene 62 10 3 64  3-10 3 65  30-100 10-30 66 <3 <367 10-30 10-30 69 10  3-10 73  3-10  3-10 80 10  3-10 81 10-30  3-10 82 3-10 10-30 83 10 10-30 84 <3 <3 85 3 10-30 86 10-30 10 87  3-10  3-1090  30-100 10-30 94  30-100 10 100 3 10 102 30 10-30 105 30 10-30 108 3010-30 113 10 <10 114  30-100 10 115  30-100 10 122 10-30 <10 123 3010-30 124 10-30 10 125 <10 <10

[0123] TABLE 6 IC₅₀ (μM) in mediator liberation from human basophils Ex.no. histamine leukotriene 127 10-30 10 128 not done 10-30 134 3 3 136 30-100 10-30 137 10-30 3 138 10-30 10 139  30-100 10-30 140 10  3-10141 10-30 10-30 143 <10 <10 144 10-30 10-30 145 10-30 <10 146 <10 <10147 10 <10 150 10-30  3-10 151 10-30  3-10 152  3-10 <3 154 10-30 <10155  30-100 10-30 156 10 10 157  30-100 10-30 158  30-100 10-30 161 3 3162  30-100 <10 163 10-30 10 164 10 <10 165 10-30  3-10 166 10-30  3-10

[0124] TABLE 7 IC₅₀ (μM) in mediator liberation from human basophils Ex.no. histamine leukotriene 167 10 3 168 <10 <10 169  30-100 10-30 17010-30 3 171  3-10  3-10 173 30 10 174 10-30 10 175  30-100 10 176 30-100 10-30 177 10 <3 179 10-30  3-10 180  30-100  3-10 181 10-30 <10182  30-100 10-30 183  30-100 10-30 184  30-100  3-10 185 10-30 <3 18710-30  3-10 188 10  3-10 189  3-10  3-10 190 3 10 193 30 10 195  30-10010-30 201 10 <10 202 10-30 <10 235 30 30

[0125] (3) Inhibitory Effects on the Interaction Between IgE Receptor γChain and 72 kDa Tyrosine Kinase

[0126] i) Experimental Method

[0127] RBL-2H3 cells which are a cell line generally used in studyingIgE-mediated intracellular signal transduction in mast cells andbasophils were used in this study. Tyrosine-phosphorylated peptide inthe tyrosine activation motif (TAM) region in the IgE receptor γ chainwas synthesized by Peptide Institute.

[0128] In the experiment, cell lysates or cytosolic fraction of RBL-2H3cells were used. Cell lysates were prepared by solubilizing 1×10⁷ to5×10⁷ cells with a solution containing various protease inhibitors and1%-NP-40 as a solubilizer. Separately, the cells were homogenized in aDowns homogenizer and centrifuged at 50,000 rpm for 1 hr, and theresulting supernatant was used as the cytosol fraction of the cells. Theconcentration of the lysate or cytosol was adjusted to 1 mg protein/mlwith an isotonic buffer. The phosphorylation experiment of the 72 kDatyrosine kinase contained in the lysate or cytosol was carried out inthe following manner.

[0129] An assay buffer [150 mM NaCl, 10 mM KCl, 20 mM Tris (pH 7.5), 0.6mM MnCl₂, 0.5 mM EGTA, 5 mM NaF, 1 mM sodium pyrophosphate and 1 mMsodium orthovanadate] containing the lysate or cytosol in an amountcorresponding to 10 mg of protein was incubated together with thecompound 101 at 30° C. for 3 min. After adding 50 mM of the peptide inthe TAM region containing the phosphorylated tyrosine and 50 mM of ATP,the incubation was further effected at 30° C. for 15 min. After thecompletion of the reaction, the sample was electrophoresed on a 10%agarose gel and a tyrosine kinase of 72 kDa was separated. Theactivation of this kinase was confirmed by examining the phosphorylationof the tyrosine moiety in the kinase per se by western blotting with theuse of anti-tyrosine phosphorylation antibody. Then the extent of thephosphorylation was numerically expressed by using an image analyzer andthus the tyrosine kinase phosphorylation inhibitory ratio of thecompound 101 was determined

[0130] ii) Results of the Experiment

[0131] The results are given in Table 8. TABLE 8 Effect of inhibitingbinding of IgE receptor γ chain to tyrosine kinase of 72 kDa Conc. ofEx. no. Compd. (μM) Inhibitory strength (%) 22 10 80 124 10 100 127 10100

[0132] (4) Effect of Inhibiting Activation (Phosphorylation) of TyrosineKinase of 72 kDa due to Antigenic Stimulation in RBL-2H3 Cells

[0133] i) Experimental method

[0134] RBL-2H3 cells were incubated for 10 min together with a testcompound in a PBS buffer containing 0.1% of BSA and 1 mM of calcium.Next, the cells were reacted with an antigen specific for the IgEreceptor for 10 min. After the completion of the antigenic stimulation,the cells were allowed to stand in ice for 1 hr in a 10 mM phosphatebuffer (pH 7.5) containing a lysis buffer (1% Triton X-100, 0.1% SDS,0.5% sodium deoxycholate, 50 mM NaCl, 50 mM NaF, 1 mM phenylmethylsulfonyl fluoride, 50 μg/ml eupeptin, 10 unit/ml aprotonin) and 0.1% ofNaN₃ followed by centrifugation to give a cell lysate. This lysate wasdiluted with a buffer for electrophoresis, heated (95° C., 5 min) andthen electrophoresed on a 10% SDS-polyacrylamide gel. After theelectrophoresis, the sample was electrically transcribed onto a 0.2 μmnitrocellulose membrane and treated with an anti-phosphotyrosineantibody for 1 hr. Then the inhibitory activity was evaluated by thecoloring analysis through chemiluminescence.

[0135] ii) Results of the Experiment

[0136] The results are given in Table 9. TABLE 9 Effect of inhibitingactivation (phosphorylation) of tyrosine kinase of 72 kDa due toantigenic stimulation in RBL-2H3 cells Conc. of Inhibitory Ex. no.Compd. (μM) Strength (%) 8 3 100 22 3 100 94 3 100 104 3 100 105 3 100115 10  80 124 10 100 127 10 100 123 30 100 129 3 100 132 3 100 138 10100 139 10 100 143 10 100 179 10 100 196 30  30 200 30  70 201 30 30-70202 30  80 235 3 100 236 3  70 262 30 100

[0137] These results indicate that the compounds of the presentinvention would inhibit the binding of the IgE receptor γ chain to thetyrosine kinase of 72 kDa and thus suppress the liberation of chemicalmediators such as serotonin, histamine and leukotrienes.

[0138] Therefore, the compounds of the present invention are usable aspreventives or remedies for diseases against which the effect ofinhibiting binding of the IgE receptor γ chain to a tyrosine kinase of72 kDa is efficacious. More particularly speaking, the compounds of thepresent invention are usable as preventives or remedies for diseasescaused by the liberation of chemical mediators such as serotonin,histamine and leukotrienes. Still particularly, these compounds areuseful in preventing or treating allergic diseases such as asthma,allergic rhinitis, atopic dermatitis, urticaria, hay fever,gastrointestinal allergy or food allergy.

[0139] Moreover, the compounds of the present invention are useful fromthe viewpoint the low toxicity and high safety thereof.

[0140] When the compounds of the present invention are used for theabove-mentioned diseases, they may be administered both orally andparenterally in the dosage form of tablets, powders, granules, capsules,syrups, troches, inhalants, suppositories, injections, ointments,ophthalmic ointments, eye drops, nasal drops, ear drops, cataplasmas,lotions, etc.

[0141] The administration dose widely varies depending on the type ofthe disease, the severity of the symptoms, the age, sex and drugsensitivity of the patient. In general, such a compound is administeredin a daily dose of from about 0.03 to 1,000 mg, preferably from 0.1 to500 mg and still preferably from 0.1 to 100 mg once to several times aday. In the case of injections, the dose usually ranges from about 1μg/kg to 3,000 μg/kg, preferably from about 3 μg/kg to 1,000 μMg/kg.

[0142] The compounds of the present invention may be processed intopreparations by conventional methods with the use of conventionalpharmaceutical carriers.

[0143] Namely, solid preparations for oral administration are preparedby mixing the principal agent with fillers, binders, disintegratingagents, lubricants, coloring agents, corrigents, antioxidants, etc. andthen processed into tablets, coated tablets, granules, powders,capsules, etc. by conventional methods.

[0144] Examples of the above-mentioned fillers are lactose, corn starch,sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc.

[0145] Examples of the binders are polyvinyl alcohol, polyvinyl ether,ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of the lubricants are magnesium stearate,talc, polyethylene glycol, silica, hardened vegetable oils, etc.

[0146] The coloring agents are those admitted to be added to medicines.Examples of the corrigents include cocoa powder, menthol, aromaticpowder, peppermint oil, borneol and powdered cinnamon bark. As theantioxidants, use can be made of any pharmaceutically authorized onessuch as ascorbic acid and a -tocopherol. Needless to say, tablets andgranules may be appropriately coated with sugar, gelatin, etc., ifnecessary.

[0147] Meanwhile, injections, eye drops, etc. can be prepared byblending the principal agent with, if needed, pH regulating agents,buffer agents, suspending agents, dissolution aids, stabilizers,tonicity agents, antioxidants, preservatives, etc. and then processed ina conventional manner. In such a case, it is also possible, if needed,to give freeze-dried preparations. Injections may be intravenously,hypodermically or intramuscularly administered.

[0148] Examples of the above-mentioned suspending agents includemethylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia,tragacanth, sodium carboxymethylcellulose and polyoxyethyelne sorbitanmonolaurate.

[0149] Examples of the dissolution aids are polyoxyethylene-hardenedcastor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitanmonolaurate, etc.

[0150] Examples of the stabilizers usable herein include sodium sulfite,sodium metasulfite and ether. Examples of the preservatives usableherein include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbicacid, phenol, cresol and chlorocresol.

[0151] Ointments can be produced by blending the principal agent with,if needed, stabilizers, antioxidants, preservatives, etc. and processedin a conventional manner.

EXAMPLES

[0152] To illustrate the present invention, the following Examples willbe given, though it is needless to say that the present invention is notrestricted thereto. Analogous compounds synthesized by similarprocedures are listed in tables. The synthesized sulfoxide compounds areall mixtures of optical isomers. The ¹H-NMR data sometimes do notinvolve active hydrogen in the compounds. In the table, each numbergiven at the lower left of the structural formula means the Examplenumber. Prior to the Examples of the compounds of the present invention,Production Examples of the starting compounds will be given.

Production Example 1

[0153] 1,2-Dimethl-10-(3-chloropropyl)phenothiazine

[0154] To a solution of 5.0 g of 1,2-dimethylphenothiazine inN,N′-dimethylformamide was added 970 mg of sodium hydride under stirringat room temperature. After stirring at room temperature for 30 min, 4.0g of 1-chloro-3-iodopropane was added dropwise followed by stirring atroom temperature overnight. After adding water, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand dried over anhydrous magnesium sulfate. After evaporating thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography to give 3.4 g of the title compound.

[0155]¹H-NMR, (400 MHz, CDCl₃) δ

[0156]7.18-7 14 (m, 2H), 7.11-7.07 (m, 1H), 6.09-6. 94 (m, 1H), 6.92 (d,J=8, 1H), 6.85 (d, J=8, 1H), 4.00-3.90 (m, 1H), 3.80-3.60 (m, 1H),3.62-3.55 (m, 2H), 2.55 (s, 3H), 2.50 (S, 3H), 2.06-1.96 (m, 2H)

Production Example 2

[0157] 1,2-Dimethyl-10-(3-phtalimidopropyl)phenothiazine

[0158] 3.4 g of 1,2-dimethyl-10-(3-chloropropyl)phenothiazine obtainedin Production Example 1 and 6.2 g of potassium phthalimide weredissolved in 100 ml of N,N′-dimethylformamide and stirred at 60° C. for40 hr. After adding water, the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 4.4 g of the title compound.

[0159]¹H-NMR,(400 MHz, CDCl₃) δ

[0160] 7.82-7.76 (m, 2H), 7.70-7.65 (m, 2H), 7.16-7.08 (m, 3H),6.98-6.93 (m, 1H), 6.89 (d, J=8, 1H), 6.82 (d, J=8, 1H), 3.85-3.72 (m,2H), 3.68 (t, J=7, 2H), 2.25 (s, 3H), 2.21 (S, 3H), 2.02-1.85 (m, 2H).

Production Example 3

[0161] 1,2-Dimethyl-10-(3-chloropropyl)phenothiazine-5-oxide

[0162] 21.3 g of 1,2-dimethyl-10-(3-chloropropyl)phenothiazine obtainedin Production Example 1 was dissolved in dichloromethane and 18.0 g of3-chlorobenzoic acid was added thereto at 0° C. After stirring at thesame temperature for 1 hr, the reaction mixture was poured into asaturated aqueous solution of sodium bicarbonate and extracted withethyl acetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 13.05 g of the title compound.

[0163]¹H-NMR,(400 MHz, CDCl₃) δ

[0164] 7.78 (d, J=8, 1H), 7.59 (d, J=8, 1H), 7.56-7.52 (m, 2H),7.23-7.17 (m, 1H), 7.15 (d, J=8, 1H), 4.43 (m, 1H), 4.19 (m, 1H)3.54-3.43 (m, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.11-1.93 (m, 2H)

Production Example 4

[0165] 1,2-Dimethyl-10-(3-phthalimidopropyl)phenothiazine-5-oxide

[0166] To a solution of 1.25 g of1,2-dimethyl-10-(3-phthalimidopropyl)phenothiazine obtained inProduction Example 2 in methylene chloride (15 ml) was added under icecooling 510 mg of 3-chloroperbenzoic acid and the mixture was stirredunder ice cooling for 1 hr. After adding water, the reaction mixture wasextracted with dichloromethane. The organic layer was washed with asaturated aqueous solution of sodium bicarbonate and an aqueous solutionof sodium chloride and then dried over anhydrous magnesium sulfate.After evaporating the solvent under reduced pressure, the residue waspurified by silica gel column chromatography to give 1.19 q of the titlecompound.

[0167]¹H-NMR,(400 MHz, CDCl₃) δ

[0168] 7.81-7.79 (m, 2H), 7.78-7.75 (m, 1H), 7.70-7.68 (m, 2H), 7 56 (d,J=8, 1H), 7.51-7.45 (m, 2H), 7.21-7.17 (m, 1H), 7.13 (d, J=8, 1H),4.30-4.18 (m, 1H), 4.07-3.99 (m, 1H), 3.62 (t, J=7, 2H) 2.36 (S, 6H),1.94-1.88 (m, 2H).

Production Example 5

[0169] 1,2-Dimethyl-10-[2-(2tetrahydropyranloxy)ethyl]phenothiazine

[0170] The procedure of Production Example 1 was repeated while using1-iodo-2-(2-tetrahydropyranyloxy)ethane instead of1-chloro-3-iodopropane to give the title compound.

[0171]¹H-NMR,(400 MHz, CDCl₃) δ

[0172] 7.15-7.10 (m, 3H), 6.98-6.92 (m, 1H), 6.90 (d, J=8, 1H), 6.83 (d,J=8, 1H), 4.49-4.44 (m, 1H), 4.04-3.65 (m, 4H), 3.58-3.48 (m, 1H),3.43-3.36 (m, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 1.75-1.63 (m, 1H),1.63-1.35 (m, 4H), 1.35-1.20 (m, 1H).

Production Example 6

[0173] 1,2-Dimethyl-10-(2-hydroxyethyl)phenothiazine

[0174] 2.2 g of1,2-dimethyl-10-[2-(2-tetrahydropyranyloxy)ethyl]phenothiazine obtainedin Production Example 5 was dissolved in 50 ml of ethanol. After addinga catalytic amount of pyridiniump-toluenesulfonate, the mixture wasstirred at 50° C. for 2 hr. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 1.45 g of the title compound.

[0175]¹H-NMR,(400 MHz, CDCl₃) δ 7.24-7.16 (m, 2H), 7.13 (d, J=8, 1H),7.00 (d, J=8, 1H), 6.98 (d, J=8, 1H), 6.96 (d, J=8, 1H), 4.08 (m, 1H),3.83-3.72 (m, 1H), 3.68-3.56 (m, 1H), 3.56-3.45 (m, 1H), 2.79 (t, J=6,1H), 2, 28 (s, 3H), 2.25 (s, 3H).

Production Example 7

[0176] 1,2-Dimethy-1,10 (2-phtbalimidoethyl)phenothiazine

[0177] 1.45 g of 1,2-dimethyl-10-(2-hydroxyethyl)phenothiazine obtainedin Production Example 6, 1.42 g of triphenylphosphine and 0.8 g ofphthalimide were dissolved in 20 ml of dry tetrahydrofuran. After adding0.85 ml of diethyl azodicarboxylate at 0° C., the reaction mixture wasstirred at room temperature for 12 hr. After adding water, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith water and then dried over anhydrous magnesium sulfate. Afterevaporating the solvent under reduced pressure, the residue was purifiedby silica gel column chromatography to give 1.95 g of the titlecompound.

[0178]¹H-NMR,(400 MHz, CDCl₃) δ

[0179] 7.80-7.73 (m, 2H), 7.70-7.65 (m, 2H), 7, 20 (m, 2H), 7.14 (d,J=7, 1H), 7.01-6.94 (m, 1H), 6.84 (d, J=8, 1H), 6.80 (d, J=8, 1H),4.11-3.81 (m, 4H), 2, 24 (s, 3H), 2.23 (s, 3H).

Production Example 8

[0180] 1,2-Dimethyl-10-(2-bromoethyl)phenothiazine

[0181] 0.5 g of 1,2-dimethyl-10-(2-hydroxyethyl)phenothiazine obtainedin Production Example 6, 0.58 g of triphenylphosphine and 0.9 g ofcarbon tetrabromide were dissolved in 10 ml of dichloromethane followedby stirring at room temperature for 1.5 hr. Then the reaction mixturewas purified by silica gel column chromatography to give 0.55 g of thetitle compound.

[0182]¹H-NMR, (400 MHz, CDCl₃) δ

[0183] 7.20-7.18 (m, 3H), 7.02 (m, 1H), 6.93 (d, J=8, 1H), 6.89 (d, J=8, 1H), 4.01 (m, 1H), 3.80 (m, 1H), 3.40 (m, 2H), 2.30 (s, 3H), 2.23(s, 3H).

Production Example 9

[0184] 3,4-Dimethyl-9-methylene-10-(3-bromopropyl)acridan

[0185] 0.1 g of 3,4-dimethyl-10-(3-bromopropyl)-9-acridone was dissolvedin 5 ml of dry tetrahydrofuran. Then 0.36 ml of methyllithium (a 1.4 Msolution in diethyl ether) was added dropwise at −78° C. After stirringat the same temperature for 1 hr, water was added to the liquid reactionmixture followed by extraction with ethyl acetate. The organic layer waswashed with water and dried over anhydrous magnesium sulfate. Afterevaporating the solvent under reduced pressure, the residue was purifiedby silica gel column chromatography to give 0.1 g of the title compound.

[0186]¹H-NMR,(400 MHz, CDCl₃) δ

[0187] 7.54 (dd, J=8, 1,1H), 7.33 (d, J=8, 1H), 7, 28 (m, 1H), 7.23 (dd,J=8, 1,1H), 7.04 (m, 1H), 6.95 (d, J=8, 1H), 5.39 (s, 1H), 5.30 (s, 1H),3.95 (t, J=7, 2H), 3.12 (t, J=7, 2H), 2.33 (s, 3H), 2.30 (s, 3H), 1.81(m, 2H).

Production Example 10

[0188] 3,4Dimethyl-9-chloro-10-(3-phthalimidopropyl)acridinium Chloride

[0189] A mixture of 1.0 g of3,4-dimethyl-10-(3-phthalimidopropyl)-9-acridone with 340 ml of oxalylchloride was stirred at room temperature in 100 ml of dichloromethanefor 30 min. After evaporating the excessive oxalyl chloride anddichloromethane under reduced pressure, 1.1 g of the title compound wasobtained.

Production Example 11

[0190](E,Z)-3,4-Dimethyl-10-(3-phthalimidopropyl)-9-acridoneoxime-O-methylEster

[0191] 1.1 g of 3,4-dimethyl-9-chloro-10-(3-phthalimidopropyl)acridiniumchloride obtained in Production Example 10 was dissolved in 50 ml ofacetonitrile. After adding 250 mg of methoxamine hydrochloride, theresulting mixture was stirred at room temperature for 20 min. Afteradding water, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. After evaporating the solvent under reduced pressure, theresidue was purified by silica gel column chromatography to give 480 mgof the title compound as a mixture of the E- and Z-enantiomers (1:1).

[0192]¹H-NMR,(400 MHz, CDCl₃) δ

[0193] 8.42 (dd, J=8, 2, 0.5H), 8.28 (d, J=8, 0.5H), 7.80-7.76 (m,2.5H), 7.68-7.66 (m, 2H), 7.58 (d, J=8, 0.5H), 7.36-7.21 (m, 2H)7.06-7.02 (m, 1H), 7.14 (d, J=8, 1H), 4.05 (s, 1.5H), 4.04 (s, 1.5H),4.00-3.90 (m, 2H), 3.48 (t, J=7, 2H), 2.31-2.28 (m, 6H) 1.70-1.60 (m,2H)

Production Example 12

[0194] 2-(Nitrophenyl)amino-3,4-dimethylbenzoic Acid

[0195] 10 g of 3,4-dimethyl-2-iodobenzoic acid, 6 g of 2-nitroaniline,250 mg of powdery copper and 25 g of potassium carbonate were added toN,N-dimethylformamide and heated under reflux while stirring for 2 hr.Then the reaction mixture was cooled to room temperature and dilutedwith water. After adjusting the pH value thereof to pH 4 with conc.hydrochloric acid, it was extracted with ethyl acetate. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.After evaporating the solvent under reduced pressure, the residue waspurified by silica gel column chromatography to give 2.5 g of the titlecompound.

[0196]¹H-NMR,(400 MHz, CDCl₃) δ

[0197] 8.13 (dd, J 8, 1,1H), 7.84 (d, J=8, 1H), 7.26 (m, 1H), 7.13 (d,J=8, 1H), 6.72 (m, 1H), 6.36 (dd, J=8, 1, 1H), 2.36 (s, 3H) 2.03 (s,3H).

Production Example 13

[0198] (5,11-Dihydro-3,4-dimethyl-11-oxo-10H-dibenzo[b,e]-1,4-diazepine

[0199] 2.5 g of 2-(nitrophenyl)amino-3,4-dimethylbenzoic acid obtainedin Production Example 12 was dissolved in 47.4 ml of methanol and 94.7ml of a 2 N aqueous ammonia and 1.44 g of sodium hydrosulfite were addedthereto. After stirring at room temperature overnight, water was addedto the reaction mixture and the pH value of the mixture was adjusted topH 4 with conc. hydrochloric acid. After extracting with ethyl acetate,the organic layer was washed with brine and dried over anhydrousmagnesium sulfate. After evaporating the solvent under reduced pressure,the residue was dissolved in 100 ml of xylene and heated under refluxfor 2 hr. After cooling, the solvent was evaporating and the residue waspurified by silica gel column chromatography to give 850 mg of the titlecompound.

[0200]¹H-NMR,(400 MHz, CDCl₃) δ

[0201] 7.84 (s, 1H), 7.68 (d, J 8, 1H), 7.05-6.97 (m, 2H), 6.93-6.87 (m,2H), 6.85 (d, J=8, 1H), 5.62 (s, 1H), 2.31 (s, 3H), 2.30 (s, 3H)

Production Example 14

[0202]5,11-Dihydro-3,4,10-trimethyl-11-oxo-10H-dibenzo[b,e]-1,4-diazepine

[0203] 850 mg of5,11-dihydro-3,4-dimethyl-11-oxo-10H-dibenzo[b,e]-1,4-diazepine obtainedin Production Example 13 was dissolved in 15 ml of tetrahydrofuran and3.75 ml of a 1 M solution of bis(trimethylsilyl)lithiumamide intetrahydrofuran was added thereto. After stirring at room temperaturefor 10 min, 0.27 ml of iodomethane was added thereto and the resultingmixture was stirred at room temperature for 1 hr. After adding water,the reaction mixture was extracted with ethyl acetate. The organic layerwas washed with brine and dried over anhydrous magnesium sulfate. Afterevaporating the solvent under reduced pressure, the residue was purifiedby silica gel column chromatography to give 540 mg of the titlecompound.

[0204]¹H-NMR,(400 MHz, CDCl₃) δ

[0205] 7.61 (d, J=8, 1H), 7.18 (dd, J=8, 2, 1H), 7.09 (m, 1H), 7.04 (m,1H), 6.92 (dd, J=8, 2,1H), 6.85 (d, J 8, 1H), 5.62 (s, 1H) 3.54 (s, 3H),2.30 (s, 6H)

Production Example 15

[0206]5-(3-Bromopropyl)-2,11-dihydro-3,4,10-trimethyl-11-oxo-10H-dibenzo[b,e]-1,4-diazepine

[0207] 800 mg of5,11-dihydro-3,4,10-trimethyl-11-oxo-10H-dibenzo[b,e]-1,4-diazepineobtained in Production Example 14 was dissolved in 20 ml oftetrahydrofuran and 1.7 ml of a 2.5 M solution of n-butyllithium inhexane was added thereto at −40° C. Then the internal temperature waswarmed to 10° C. over 20 min and 1.24 g of 3-bromo-1-propanoltrifluoromethanesulfonate was added thereto followed by stirring at roomtemperature for 30 min. After adding water, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried over anhydrous magnesium sulfate. After evaporating thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography to give 830 mg of the title compound.

[0208]¹H-NMR,(400 MHz, CDCl₃) δ

[0209] 7.56 (d, J=8, 1H), 7.30 (dd, J=8, 2, 1H), 7.24-7.18 (m, 2H)7.15-7. 09 (m, 1H), 704 (d, J=8, 1H), 3.63-3.49 (m, 2H), 3.60 (s, 3H),3.48-3.39 (m, 2H), 2.39 (s, 3H), 2.28 (s, 3H), 2.03-1.94 (m, 2H).

Example 1

[0210] 1 2-Dimethyl-10-(3-aminopropyl)phenothiazine

[0211] 100 ml of a solution of 1.6 g of1,2-dimethyl-10-(3-phthalimidopropyl)phenothiazine obtained inProduction Example 2 and 2.0 ml of hydrazine monohydrate in methanol wasstirred under reflux for 4 hr. After evaporating the solvent underreduced pressure, the residue was basified with a 1 N aqueous solutionof sodium hydroxide and extracted with dichloromethane. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.After evaporating the solvent under reduced pressure, the residue waspurified by silica gel column chromatography to give 870 mg of the titlecompound.

[0212]¹H-NMR,(400 MHz, CDCl₃) δ

[0213] 7.16-7.12 (m, 2H), 7.08 (dd, J=1.2, 8,1H), 6.97-6.92 (m, 1H) 6.90(d, J=8, 1H), 6.83 (d, J=8, 1H), 3.90-3.78 (m, 1H), 3.66-3.50 (m, 1H),2.69 (t, J=7, 2H), 2.25 (s, 3H), 2.23 (s, 3H) 1.76-1.68 (m, 2H).

[0214] The following compounds were obtained by the same procedure asthe one of Example 1. TABLE 10 Ex. no. ¹H-NMR(400 MHz)δ

CDCl₃7.20(d, J=2, 1H), 7.06(dd, J=2, 8, 1H), 6.98(d, J=8, 1H), 6.89(d,J=8, 1H), 6.84(d, J=8, 1H), 3.90-3.78(m, 1H), 3.64-3.50(m, 1H), 2.67(t,J=7, 2H), 2.23(s, 6H), 1.75-1.68(m, 2H)

CDCl₃7.43(t, J=8, 1H), 7.35(d, J=8, 1H), 7.10-6.98(m, 4H), 6.92-6.80(m,3H), 5.20-4.80(m, 2H), 3.86(s, 2H), 2.35(s, 3H), 2.23(s, 3H)

Example 4

[0215] 1,2-Dimethyl-10-(3-benzylaminopropyl)phenothiazine

[0216] The procedure of Production Example 1 was repeated while using3-bromopropyl trifluoromethanesulfonate instead of1-chloro-3-iodopropane to give1,2-dimethyl-10-(3-bromopropyl)phenothiazine. 50 ml of a solution of 400mg of the resulting compound and 370 mg of benzylamine in ethanol wasstirred at 70° C. for 30 min. Then the reaction mixture was cooled toroom temperature and a saturated aqueous solution of sodium bicarbonatewas added thereto. After extracting with ethyl acetate, the organiclayer was washed with brine and dried over anhydrous magnesium sulfate.After evaporating the solvent under reduced pressure, the residue waspurified by silica gel column chromatography to give 40 mg of the titlecompound.

[0217]¹H-NMR, (400 MHz, CDCl₃) δ

[0218] 7.30-7.10 (m, 7H), 7.07-7.04 (m, 1H) 6.96-6.91 (m, 1H), 6.88 (d,J=8, 1H), δ 82 (d, J=8, 1H), 3.90-3.80 (m, 1H), 3.67 (s, 2H) 3.64-3.54(m, 1H), 2.66 (t, J=7, 2H), 2.23 (s, 3H), 2.22 (s, 3H) 1.84-1.76 (m,2H).

[0219] The following compounds were obtained by the same procedure asthe one of Example 4. TABLE 11 Ex. no. ¹H-NMR(400 MHz)δ

CDCl₃7.34-7.26(m, 3H), 7.17-7.11(m, 4H), 7.03(dd, J=1, 8, 1H),6.97-6.93(m, 1H), 6.87(d, J=8, 1H), 6.84(d, J=8, 1H), 3.96-3.88(m, 1H),3.82(s, 2H), 3.60-3.46(m, 1H), 3.18(s, 2H), 3.00-2.80(m, 2H), 2.23(s,3H), 2.20(s, 3H), 1.90-1.78(m, 2H)

CDCl₃7.45(t, J=8, 1H), 7.38(d, J=8, 1H), 7.35-7.23(m, 5H), 7.08-6.98 (m,4H), 6.90-6.80(m, 3H), 5.20-4.80(m, 2H), 3.82(s, 2H), 3.75(s, 2H),2.35(s, 3H), 2.23(s, 3H)

CDCl₃7.47(t, J=8, 1H), 7.26(d, J=8, 1H), 7.11-7.01(m, 4H), 6.95(s, 2H),6.88-6.79(m, 3H), 5.20-4.80(m, 2H), 3.83(s, 2H), 3.77(s, 2H), 2.37(s,3H), 2.21(s, 3H)

Example 8

[0220] 1,2-Dimethyl-10-(3-aminopropyl)phenothiazine-5-oxide

[0221] 50 ml of a solution of 1.19 g of1,2-dimethyl-10-(3-phthalimidopropyl)phenothiazine-5-oxide obtained inProduction Example 4 and 1.5 ml of hydrazine monohydrate in methanol wasstirred at 40° C. for 2 hr. After evaporating the solvent, the residuewas extracted with dichloromethane. After evaporating the solvent underreduced pressure, 700 mg of the title compound was obtained.

[0222]¹H-NMR, (400 MHz, CDCl₃) δ

[0223] 7.75 (dd, J 1, 8, 1H), 7.72-7.68 (m, 1H), 7.60-7.55 (m, 1H), 7.55(d, J=8, 1H), 7.22-7.16 (m, 2H), 4.36-4.26 (m, 1H), 4.02-3.92 (m, 1H),2.39 (t, J=7, 2H), 2.34 (s, 3H), 2.33 (s, 3H) 1.45-1.38 (m, 2H).

[0224] The following compounds were obtained by the same procedure asthe one of Example 8. TABLE 12 Ex. no. ¹H-NMR(400 MHz)δ

DMSO-d6 7.64(d, J=8, 1H), 7.55-7.53(m, 2H), 7.15(d, J=8, 1H), 7.06(dd,J=1, 8, 1H), 4.36-4.26(m, 1H), 4.00-3.90(m, 1H), 3.65(t, J=7, 2H),2.80(t, J=7, 2H), 2.39(t, J=7, 2H), 2.34(s, 3H), 2.32(s, 3H),1.50-1.32(m, 2H)

CDCl₃7.64(d, J=2, 1H), 7.62(d, J=8, 1H), 7.56(dd, J=8, 2, 1H), 7.30(dd,J=2, 8, 1H), 7.15(d, J=8, 1H), 4.28-4.18(m, 1H), 4.06-3.98 (m, 1H),2.61(t, J=7, 2H), 2.37(s, 6H), 1.72-1.50(m, 2H)

CDCl₃7.66(d, J=8, 1H), 7.54(d, J=8, 1H), 7.40(dd, J=1, 6, 1H), 7.11(d,J=8, 1H), 7.08-7.05(m, 1H), 4.61-4.56(m, 1H), 4.40-4.30 (m, 1H),4.05-3.96(m, 2H), 3.81-3.70(m, 1H), 3.69-3.60(m, 1H), 3.50-3.40(m, 1H),2.98(t, J=7, 2H), 2.66-2.56(m, 2H), 2.37(s, 3H), 2.36(s, 3H),1.84-1.64(m, 4H), 1.60-1.40(m, 4H)

DMSO-d6 8.40(d, J=2, 1H), 8.01(dd, J=2, 8, 1H), 7.91(d, J=8, 1H),7.66(d, J=8, 1H), 7.27(d, J=8, 1H), 4.58-4.47(m, 1H), 4.12-4.03 (m, 1H),2.43(t, J=7, 2H), 2.37(s, 6H), 1.53-1.37(m, 2H)

DMSO-d6 7.70(d, J=8, 1H), 7.56(d, J=8, 1H), 7.23(d, J=2, 1H), 7.17(d,J=8, 1H), 6.80(dd, J=2, 8, 1H), 4.48-4.35(m, 1H), 4.00-3.88(m, 1H),3.88(s, 3H), 2.40-2.28(m, 2H), 2.36(s, 3H), 2.35(s, 3H), 1.65-1.43(m,2H)

DMSO-d6 7.64(d, J=8, 1H), 7.56(d, J=8, 1H), 7.55(s, 1H), 7.17(d, J=8,1H), 7.03(d, J=8, 1H), 4.40-4.27(m, 1H), 4.02-3.91(m, 1H), 2.46-2.38 (m,2H), 2.42(s, 3H), 2.35(s, 3H), 2.34(s, 3H), 1.56-1.37(m, 2H)

DMSO-d6 7.88(d, J=2, 1H), 7.80(d, J=8 1H), 7.59(d, J=8, 1H), 7.26(dd,J=2, 8, 1H), 7.22(d, J=8, 1H), 4.46-4.32(m, 1H), 4.05-3.95(m, 1H),2.48-2.40(m, 2H), 2.36(s, 3H), 2.35(s, 3H), 1.52-1.38(m, 2H)

[0225] TABLE 13 Ex. no. ¹H-NMR(400 MHz)δ

CDCl₃7.74(d, J=2, 1H), 7.57(d, J=8, 1H), 7.46-7.40(m, 2H), 7.15(d, J=8,1H), 4.20(m, 1H), 4.00(m, 1H), 2.59(t, J=7, 2H), 2.38(s, 3H), 2.38(s,3H), 1.64(m, 2H)

CDCl₃7.56(d, J=8, 1H), 7.50-7.42(m 2H), 7.21(m, 1H), 7.15(d, J=8, 1H),4.12(m, 1H), 4.00(m, 1H), 2.59(t, J=7, 2H), 2.38(s, 3H), 2.37(s, 3H),1.62(m, 2H)

CDCl₃7.62(d, J=8, 1H), 7.46-7.38(m, 2H), 7.18-7.12(m, 2H), 4.40(m, 1H),4.00(m, 1H), 2.61(m, 2H), 2.39(s, 3H), 2.38(s, 3H), 1.70(m, 2H)

DMSO-d6 8.11(dd, J=2, 8, 1H), 7.74(d, J=8, 1H), 7.63-7.59(m, 1H),7.20-7.16 (m, 1H), 7.04(s, 1H), 4.51-4.42(m, 1H), 3.92-3.82(m, 1H),2.63(s, 3H), 2.48-2.37(m, 2H), 2.32(s, 3H), 2.30(s, 3H), 1.55-1.38 (m,2H)

CDCl₃7.76(m, 1H), 7.50-7.44(m, 2H), 7.18(m, 1H), 7.15(s, 1H), 4.17(m,1H), 3.95(m, 1H), 3.90(s, 3H), 2.58(t, J=7, 2H), 2.39(s, 3H), 2.22(s,3H), 1.60(m, 2H)

7.68(dd, J=8, 2, 1H), 7.60(d, J=8, 1H), 7.28-7.35(m, 2H), 7.15 (d, J=9,1H), 7.15(d, J=8, 1H), 7.08(m, 1H), 6.47(d, J=9, 1H), 5.33(d, J=15, 1H),5.11(d, J=15, 1H), 3.72(s, 3H), 3.69(s, 3H), 3.45(d, J=12, 1H), 3.36(d,J=12, 1H), 2.49(s, 3H), 2.37(s, 3H), 2.16(s, 6H)

Example 22

[0226] 1,2-Dimethyl-10-(3-benzylaminopropyl)-phenothiazine-5-oxide

[0227] A solution of 1.5 g of1,2-dimethyl-10-(3-aminopropyl)phenothiazine-5-oxide obtained in Example8 and 580 mg of benzaldehyde in 60 ml of toluene was stirred underreflux for 2 hr while using a water separator. Then the mixture wascooled to room temperature and the solvent was evaporated under reducedpressure. After adding 60 ml of ethanol and sodium borohydridesuccessively, the reaction mixture was stirred under ice cooling for 10min. After adding water, the mixture was extracted with ethyl acetate.The organic layer was washed with brine and dried over anhydrousmagnesium sulfate. After evaporating the solvent under reduced pressure,the residue was washed with diethyl ether to give 1.9 g of the titlecompound.

[0228]¹H-NMR,(400 MHz, CDCl₃) δ

[0229] 7.82 (d, J=7, 1H), 7.76 (d, J=8, 1H), 7.65-7.60 (m, 2H), 7.35 (s,5H), 7.25-7.20 (m, 2H), 4.45-4.56 (m, 1H), 4.03-3.96 (in, 1H), 3.88 (s,2H), 2.97-2.85 ((m, 1H), 2.76-2.65 (m, 1H), 2.35 (s, 3H) 2.34 (s, 3H),1.83-1.74 (m, 2H)

[0230] The following compounds were obtained in accordance with theprocedure of Example 22. TABLE 14 Ex. no. ¹H-NMR(400 MHz)δ

CDCl₃7.78(dd, J=1, 7, 1H), 7.57(d, J=7, 1H), 7.57-7.48(m, 2H),7.21-7.17(m, 1H), 7.15-7.11(m, 2H), 6.90(dd, J=1, 8, 1H), 6.79(dd, J=8,1, 1H), 6.75-6.71(m, 1H), 4.39-4.30(m, 1H), 4.03-4.00(m, 1H), 3.83(d,J=14, 1H), 3.79(d, J=14, 1H), 2.55(t, J=7, 2H), 2.38(s, 6H),1.84-1.72(m, 2H)

CDCl₃7.74(dd, J=1, 8, 1H), 7.54(d, J=8, 1H), 7.52-7.45(m, 2H),7.17-7.13(m, 1H), 7.10(d, J=8, 1H), 6.98(t, J=8, 1H), 6.60-6.52(m, 3H),4.38-4.27(m, 1H), 4.01-3.82(m, 1H), 3.44(s, 2H), 2.56-2.41 (m, 2H),2.33(s, 6H), 1.85-1.69(m, 2H)

CDCl₃7.75(d, J=8, 1H), 7.56(d, J=8, 1H), 7.54-7.48(m, 2H), 7.18-7.15 (m,1H), 7.13(d, J=8, 1H), 6.87(d, J=8, 2H), 6.41(d, J=8, 2H), 4.43-4.36(m,1H), 4.08-3.98(m, 1H), 3.56(d, J=12, 1H), 3.51(d, J=12, 1H),2.68-2.59(m, 2H), 2.34(s, 3H), 2.35(s, 3H), 2.00-1.82(m, 2H)

CDCl₃7.78(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.55-7.50(m, 2H), 7.21-7.17(m, 1H), 7.14(d, J=8, 1H), 7.01(d, J=8, 1H), 6.75(d, J=7, 1H), 6.64(t,J=8, 1H), 4.49-4.30(m, 1H), 4.05-3.97(m, 1H), 3.79(s, 2H), 2.54(t, J=7,2H), 2.39(s, 3H), 2.38(s, 3H), 2.22(s, 3H), 1.82-1.73(m, 2H)

CDCl₃7.77(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.54-7.50(m, 2H), 7.21-7.17(m, 1H), 7.14(d, J=8, 1H), 7.79(dd, J=1, 8, 1H), 6.69(t, J=8, 1H),7.54(dd, J=1, 8, 1H), 4.41-4.28(m, 1H), 4.03-3.94(m, 1H), 3.87(s, 3H),3.87(d, J=14, 1H), 3.80(d, J=14, 1H), 2.60-2.48 (m, 2H), 2.37(s, 6H),1.83-1.74(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.58(d, J=8, 1H), 7.52-7.47(m, 2H), 7.19(m, 1H),7.13(d, J=8, 1H), 6.79(dd, J=8, 2, 1H), 6.65(t, J=8, 1H), 6.54(dd, J=8,2, 1H), 4.52(m, 1H), 4.30(m, 1H), 3.98(m, 1H), 3.82(d, J=16, 1H),3.77(d, J=16, 1H), 2.54(m, 2H), 2.37(s, 6H), 1.78(m, 2H), 1.36(d, J=6,6H)

[0231] TABLE 15 Ex. no. ¹H-NMR(400 MHz)δ

CDCl₃7.78(dd, J=8, 2, 1H), 7.58(d, J=8, 1H), 7.55-7.48(m, 2H), 7.21-7.17(m, 2H), 7.14(d, J=8, 1H), 6.77(dd, J=8, 2, 1H), 6.64(t, J=8, 1H),4.38(m, 1H), 3.98(m, 1H), 3.82(d, J=16, 1H), 3.77(d, J=16, 1H), 2.52(m,2H), 2.39(s, 6H), 1.80(m, 2H)

CDCl₃7.78(dd, J=1, 7, 1H), 7.58(d, J=8, 1H), 7.54-7.51(m ,2H), 7.36(dd,J=1, 8, 1H), 7.21-7.17(m, 1H), 7.14(d, J=8, 1H), 6.81(d, J=7, 1H),6.59(t, J=8, 1H), 4.43-4.13(m, 1H), 4.02-3.95(m, 1H), 3.78(s, 2H),2.51(t, J=7, 2H), 2.39(s, 6H), 1.83-1.75(m, 2H)

DMSO-d6 8.36(b, 1H), 7.82(dd, J=1, 8, 1H), 7.75(d, J=8, 1H), 7.64-7.60(m, 2H), 7.25-7.19(m, 2H), 7.06(dd, J=1, 7, 1H), 6.46(t, J=7, 1H),4.54-4.43(m, 1H), 4.03-3.95(m, 1H), 3.78(s, 2H), 2.96-2.88 (m, 1H),2.77-2.68(m, 1H), 2.34(s, 6H), 1.83-1.73(m, 2H)

DMSO-d6 7.82(dd, J=1, 8, 1H), 7.76(d, J=8, 1H), 7.71(s, 1H), 7.64-7.59(m, 2H), 7.25-7.19(m, 2H), 7.04(dd, J=2, 8, 1H), 7.56(d, J=8, 1H),4.55-4.43(m, 1H), 4.02-3.92(m, 1H), 3.74(s, 2H), 2.96-2.84 (m, 1H),2.76-2.65(m, 1H), 2.34(s, 6H), 1.82-1.70(m, 2H)

DMSO-d6 7.77(dd, J=1, 8, 1H), 7.71(d, J=8, 1H), 7.76-7.56(m, 1H),7.56(d, J=8, 1H), 7.23-7.17(m, 2H) 6.46-6.42(m, 2H), 6.40(s, 1H),4.40-4.29(m, 1H), 4.02-3.93(m, 1H), 3.52(s, 2H), 2.42-2.35(m, 2H),2.34(s, 3H), 2.33(s, 3H), 1.61-1.45(m, 2H)

CDCl₃7.78(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.56-7.49(m, 2H), 7.22-7.18(m, 2H), 7.15(d, J=8, 1H), 6.75(d, J=3, 1H), 4.45-4.34(m, 1H),4.01-3.92(m, 1H), 3.74(s, 2H), 2.52-2.48(m, 2H), 2.39(s, 6H),1.83-1.76(m, 2H)

[0232] TABLE 16 Ex. no. ¹H-NMR(400M Hz)δ

CDCl₃7.74(d, J=8, 1H), 7.48-7.60(m, 3H), 7.09-7.21(m, 4H), 6.81(t, J=8,1H), 4.57(s, 2H), 4.49(m, 1H), 4.10(m, 1H), 3.85(s, 2H), 3.44(s, 3H),2.72(t, J=7, 2H), 2.41(s, 3H), 2.39(s, 3H), 1.91-1.55(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.45-7.55(m, 2H), 7.18(t, J=8,1H), 7.13(d, J=8, 1H), 6.88(t, J=8, 1H), 6.24(d, J=8, 2H), 4.35(m, 1H),3.96(m, 1H), 3.83(d, J=11, 1H), 3.79(d, J=11, 1H), 2.49-2.55(m, 2H),2.39(s, 6H), 1.72-1.82(m, 2H)

CDCl₃7.77(d, J=8. 1H), 7.57(d, J=8, 1H), 7.44-7.55(m, 2H), 7.18(t, J=8,1H), 7.13(d, J=8, 1H), 6.79(d, J=8, 1H), 6.18(d, J=8, 1H), 4.33(m, 1H),3.97(m, 1H), 3.87(d, J=14, 1H), 3.82(d, J=14, 1H), 2.55(t, J=7, 2H),2.38(s, 6H), 2.10(s, 3H), 1.75-1.85(m, 2H)

CDCl₃7.73(d, J=8, 1H), 7.49-7.57(m, 3H), 7.14-7.19(m, 1H), 7.11(d, J=8,1H), 6.66(d, J=8, 1H), 6.45(d, J=8, 1H), 4.46(m, 1H), 4.05(m, 1H),3.91(s, 2H), 3.78(s, 3H), 2.63-2.78(m, 2H), 2.39(s, 3H), 2.38(s, 3H),1.91-2.10(m, 2H)

CDCl₃7.75(d, J=8, 1H), 7.49-7.61(m, 3H), 7.20(t, J=8, 1H), 7.14(d, J=8,1H), 6.63(s, 1H), 4.50(m, 1H), 4.08(m, 1H), 3.93(d, J=13, 1H), 3.90(d,J=13, 1H), 3.78(s, 3H), 2.79(m, 1H), 2.71(m, 1H), 2.40(s, 6H), 2.18(s,3H), 1.95-2.15(m, 2H)

CDCl₃7.79(dd, J=8, 2, 1H), 7.58(d, J=8, 1H), 7.49-7.56(m, 2H), 7.20(m,1H), 7.15(d, J=8, 1H), 7.08(dd, J=10, 2, 1H), 6.78(m, 1H), 4.37(m, 1H),3.97(m, 1H), 3.81(d, J=14, 1H), 3.75(d, J=14, 1H), 2.49(m, 2H), 2.39(s,6H), 1.79(m, 2H)

CDCl₃7.79(dd, J=8, 2, 1H), 7.58(d, J=8, 1H), 7.49-7.56(m, 2H), 7.33(d,J=2, 1H), 7.20(m, 1H), 7.15(d, J=8, 1H), 6.89(d, J=2, 1H), 4.39(m, 1H),3.97(m, 1H), 3.74(s, 2H), 2.49(m, 2H), 2.40(s, 6H), 1.80(m, 2H)

[0233] TABLE 17 Ex. no. ¹H-NMR(400 MHz)δ

CDCl₃7.78(dd, J=8, 2, 1H), 7.58(d, J=8, 1H), 7.49-7.56(m, 2H), 7.20(m,1H), 7.14(d, J=8, 1H), 6.91-6.97(m, 1H), 6.60-6.66(m, 2H), 4.37(m, 1H),3.98(m, 1H), 3.86(d, J=14, 1H), 3.81(d, J=14, 1H), 2.54(m, 2H), 2.39(s,6H), 1.80(m, 2H)

DMSO-d6 7.78(d, J=8, 1H), 7.59(d, J=8, 1H), 7.52-7.49(m, 2H), 7.19(m,1H), 7.14(d, J=8, 1H), 4.28(m, 1H), 4.06(m, 1H), 2.53 (m, 2H), 2.39(s,3H), 2.38(s, 3H), 2.30(d, J=7, 2H), 1.75-1.60(m, 2H), 0.82(m, 1H),0.40(m, 2H), 0.00(m, 2H)

CDCl₃7.77-7.75(m, 1H), 7.57(d, J=8, 1H), 7.49-7.46(m, 2H), 7.20-7.12 (m,4H), 7.03(dd, J=1, 8, 1H), 6.94-6.90(m, 1H), 5.14(s, 2H), 4.32-4.20(m,1H), 4.08-3.98(m, 1H), 3.67(s, 2H), 3.41(s, 3H), 2.53-2.49(m, 2H),2.37(s, 3H), 2.36(s, 3H), 1.78-1.62(m, 2H)

CDCl₃7.75-7.73(m, 1H), 7.54(d, J=8, 1H), 7.49-7.47(m, 2H), 7.19-7.11 (m,3H), 6.48(d, J=8, 2H), 4.39-4.27(m, 1H), 4.06-3.96(m, 1H), 3.79(s, 2H),3.74(s, 6H), 2.48(t, J=7, 2H), 2.37(s, 3H), 2.35(s, 3H), 1.76-1.60(m,2H)

CDCl₃7.77(d, J=8, 1H), 7.58(d, J=8, 1H), 7.48-7.53(m, 2H), 7.14-7.22 (m,2H), 7.13(d, J=8, 1H), 7.05(dd, J=2, 8, 1H), 6.86(d, J=8, 1H), 6.84(d,J=8, 1H), 4.29(m, 1H), 4.13(t, J=4, 2H), 3.98(m, 1H), 3.65-3.69(m, 2H),3.62(d, J=12, 1H), 3.57(d, J=12, 1H), 2.44-2.59(m, 2H), 2.36(s, 6H),1.69-1.81(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.56(d, J=8, 1H), 7.49-7.46(m, 2H), 7.17(m, 1H),7.12(d, J=8, 1H), 6.94(t, J=8, 1H), 6.79(dd, J=8, 2, 1H), 6.74(dd, J=8,2, 1H), 5.05(s, 2H), 4.50(m, 1H), 4.23(m, 1H), 4.05(m, 1H), 3.68(s, 2H),3.49(s, 3H), 2.51(m, 2H), 2.36(s, 3H), 2.36(s, 3H), 1.75-1.55(m, 2H),1.32(d, J=6, 6H)

CDCl₃7.76(dd, J=8, 2, 1H), 7.56(d, J=8, 1H), 7.50-7.45(m, 2H), 7.26(dd,J=8, 2, 1H), 7.18(m, 1H), 7.13(d, J=8, 1H), 7.08(dd, J=8, 2, 1H),6.98(t, J=8, 1H), 5.04(s, 2H), 4.25(m, 1H), 4.05(m, 1H), 3.69(s, 2H),3.54(s, 3H), 2.51(t, J=7, 2H), 2.36(s, 6H), 1.70(m, 2H)

[0234] TABLE 18 Ex. no. ¹H-NMR(400 MHz)

CDCl₃7.77(dd, J=8, 2, 1H), 7.57(d, J=8, 1H), 7.46-7.52(m, 2H),7.10-7.20(m, 3H), 6.57-6.63(m, 3H), 4.28(m, 1H), 4.04(m, 1H), 3.61(s,2H), 2.92(s, 6H), 2.55(t, J=7, 2H), 2.37(s, 3H), 2.36(s, 3H), 1.73(m,2H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.46-7.51(m, 2H), 7.15-7.21 (m,3H), 7.22(d, J=8, 1H), 7.06(d, J=8, 1H), 6.98(m, 1H), 4.27(m, 1H),4.08(m, 1H), 3.72(s, 2H), 2.62(s, 6H), 2.54(t, J=7, 2H), 2.37(s, 3H),2.36(s, 3H), 1.75(m, 2H)

CDCl₃7.77(dd, J=8, 2, 1H), 7.58(d, J=8, 1H), 7.44-7.55(m, 2H), 7.19(m,1H), 7.14(d, J=8, 1H), 7.06(m, 1H), 6.96(dd, J=8, 2, 1H), 6.64(m, 1H),6.59(dd, J=8, 2, 1H), 4.23(m, 1H), 4.02(m, 1H), 3.65(s, 2H), 2.56(m,2H), 2.38(s, 3H), 2.37(s, 3H), 1.77(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.47-7.53(m, 2H), 7.11-7.33 (m,6H), 4.29(m, 1H), 4.10(m, 1H), 3.73(s, 2H), 2.54(t, J=7, 2H), 2.38(s,3H), 2.37(s, 3H), 1.75(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.46-7.53(m, 2H), 7.18(ddd,J=8, 6, 2, 1H), 7.13(d, J=8, 1H), 6.72-6.77(m, 2H), 6.68(dd, J=8, 2,1H), 4.24-4.34(m, 1H), 4.22(s, 4H), 4.06(dt, J=14, 7, 1H), 3.53(s, 2H),2.53(t, J=7, 2H), 2.38(s, 3H), 2.37(s, 3H), 1.67-1.82 (m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.56(d, J=8, 1H), 7.45-7.52(m, 2H), 7.15-7.20 (m,1H), 7.12(d, J=8, 1H), 6.63-6.76(m, 3H), 5.88(s, 2H), 4.21-4.31(m, 1H),4.04(ddd, J=15, 9, 6, 1H), 3.63(S, 2H), 2.53(t, J=6, 2H), 2.37(s, 3H),2.36(s, 3H), 1.65-1.81(m, 2H)

CDCl₃7.89(dd, J=1, 7, 1H), 7.69(d, J=7, 1H), 7.51-7.45(m, 2H), 7.39(d,J=7, 1H), 7.35-7.30(m, 1H), 7.26-7.22(m, 1H), 7.16-7.12(m, 1H), 7.04(d,J=8, 2H), 4.50-4.40(m, 1H), 4.10-4.00(m, 1H), 3.78(d, J=12, 1H), 3.72(d,J=12, 1H), 2.72-2.58(m, 2H), 2.34(s, 6H), 1.92-1.82(m, 2H)

[0235] TABLE 19 Ex. no. ¹H-NMR(400 MHz)

DMSO-d6 7.80(dd, J=1, 8, 1H), 7.75(d, J=8, 1H), 7.62-7.58(m, 2H),7.31-7.27(m, 1H), 7.24-7.18(m, 2H), 7.12-7.08(m, 2H), 6.86(t, J=7, 1H),4.56-4.43(m, 1H), 4.36(d, J=16, 1H), 4.29(d, J=16, 1H), 4.14-4.02(m,1H), 3.74(s, 2H), 2.88-2.76(m, 1H), 2.74-2.72 (m, 1H), 2.34(s, 3H),2.33(s, 3H), 1.84-1.74(m, 2H)

CDCl₃7.88-7.72(m, 1H), 7.62-7.54(m, 1H), 7.42-7.30(m, 5H), 7.08-6.90(m,3H), 4.41-4.25(m, 1H), 4.02-3.90(m, 1H), 3.81(s, 2H), 3.08-2.84(m, 2H),2.20(s, 3H), 2.15(s, 3H), 2.05-1.90(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.48-7.55(m, 2H), 7.41(d, J=4,1H), 7.15-7.20(m, 1H), 7.14(d, J=8, 1H), 6.76(d, J=4, 1H), 4.37(m, 1H),4.13(m, 1H), 3.74-3.83(m, 2H), 2.48-2.61(m, 2H), 2.41(s, 3H), 2.39(s,3H), 1.68-1.77(m, 2H)

CDCl₃7.80(d, J=8, 1H×½), 7.77(d, J=8, 1H×½), 7.46-7.65(m, 3H), 7.34(d,J=5, 1H), 7.10-7.24(m, 2H), 7.04(d, J=5, 1H×½), 6.99(d, J=5, 1H×½),4.46(m, 1H×½), 4.31(m, 1H×½), 4.21(m, 1H), 4.00(dd, J=7, 17, #1H×½),3.84(m, 1H×½), 2.55(m, 1H), 2.40(s, 3H), 2.37(s, 3H×½), 2.35(s, 3H),2.21(s, 3H×½), 2.12-2.34(m, 1H), 1.65-1.90(m, 2H), 1.21(d, J=7, 3H×½),1.11(d, J=7, 3H×½)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.49-7.52(m, 2H), 7.22(d, J=5,1H), 7.15-7.20(m, 1H), 7.13(d, J=8, 1H), 6.89(d, J=5, 1H), 4.32(m, 1H),4.06(m, 1H), 3.82(d, J=14, 1H), 3.76(d, J=14, 1H), 3.35(s, 3H), 3.33(s,3H), 2.58(t, J=7, 2H), 2.39(s, 3H), 2.37(s, 3H), 1.67-1.77(m, 2H)

CDCl₃7.78(d, J=8, 1H), 7.60(d, J=8, 1H), 7.48-7.55(m, 2H), 7.15-7.20 (m,1H), 7.13(d, J=8, 1H), 7.05(d, J=5, 1H), 7.03(d, J=5, 1H), 4.37(m, 1H),4.00(m, 1H), 3.68(s, 2H), 2.84(s, 3H), 2.48(s, 2H), 2.38(s, 6H), 1.75(m,2H)

[0236] TABLE 20 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.77-7.74(m, 1H), 7.55(d, J=8, 1H), 7.52-7.49(m, 2H), 7.29(dd, J=1,2, 1H), 7.20-7.16(m, 1H), 7.14(d, J=8, 1H), 6.26(dd, J=2, 3, 1H),6.20-6.17(m, 1H), 4.38-4.30(m, 1H), 4.10-4.00(m, 1H), 3.69(s, 2H),2.56(t, J=7, 2H), 2.38(s, 3H), 2.37(s, 3H), 1.85-1.75(m, 2H)

DMSO-d6 7.75(dd, J=1, 7, 1H), 7.70(d, J=7, 1H), 7.60-7.54(m, 1H),7.56(d, J=8, 1H), 7.23-7.16(m, 2H), 6.88-6.72(m, 2H), 4.36-4.26(m, 1H),3.90-4.00(m, 1H), 3.50(s, 2H), 2.40-2.30(m, 2H), 2.33(s, 3H), 2.32(s,3H), 1.56-1.45(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.45-7.52(m, 2H), 7.18(ddd,J=8, 6, 2, 1H), 7.13(d, J=8, 1H), 5.93(d, J=3, 1H), 4.99(d, J=3, 1H),4.20-4.30(m, 1H), 3.98-4.08(m, 1H), 3.79(s, 3H), 3.50(s, 2H),2.46-2.54(m, 2H), 2.37(s, 3H), 2.36(s, 3H), 1.62-1.78(m, 2H)

CDCl₃7.74(d, J=8, 1H), 7.55(d, J=8, 1H), 7.43-7.53(m, 2H), 7.18(t, J=8,1H), 7.13(d, J=8, 1H), 6.10(d, J=3, 1H), 5.93(d, J=3, 1H), 4.48(s, 2H),4.19-4.29(m, 1H), 4.03(dt, J=14, 7, 1H), 3.58(s, 2H), 2.43-2.54(m, 2H),2.36(s, 6H), 1.64-1.74(m, 2H)

CDCl₃7.75(d, J=8, 1H), 7.56(d, J=8, 1H), 7.46-7.51(m, 2H), 7.14-7.20(m,1H), 7.12(d, J=8, 1H), 7.04(d, J=5, 1H), 6.77(d, J=5, 1H), 4.22-4.31(m,1H), 4.02-4.11(m, 1H), 3.76(s, 3H), 3.72(s, 2H), 2.54(t, J=7, 2H),2.38(s, 3H), 2.46(s, 3H), 1.63-1.79(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.58(d, J=8, 1H), 7.47-7.52(m, 2H), 7.15-7.21(m,1H), 7.13(d, J=8, 1H), 6.42(d, J=3, 1H), 5.96(d, J=3, 1H), 4.24-4.34(m,1H), 4.03-4.16(m, 1H), 3.85(s, 3H), 3.66(s, 2H), 2.54(t, J=7, 2H),2.40(s, 3H), 2.38(s, 3H), 1.64-1.77(m, 2H)

[0237] TABLE 21 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.93(d, J=8, 1H), 7.86(d, J=8, 1H), 7.77(d, J=7, 1H), 7.57(d, J=8,1H), 7.48-7.53(m, 2H), 7.45(td, J=7, 2, 1H), 7.36(t, J=8, 1H), 7.18(ddd,J=8, 6, 2, 1H), 7.12(d, J=8, 1H), 4.37(dt, J=14, 6, 1H), 4.10-4.19(m,1H), 4.06(s, 2H), 2.65(td, J=6, 2, 2H), 2.42(s, 3H), 2.37(s, 3H),1.70-1.83(m, 2H)

CDCl₃7.82(dd, J=8, 2, 1H), 7.61(d, J=8, 1H), 7.48-7.58(m, 4H), 7.34(s,1H), 7.30-7.37(m, 2H), 7.19-7.25(m, 2H), 7.15(d, J=8, 1H), 4.41(m, 1H),4.01(m, 1H), 3.83(d, J=14, 1H), 3.68(d, J=14, 1H), 2.47(t, J=7, 2H),2.37(s, 3H), 2.36(s, 3H), 1.77(m, 2H)

CDCl₃8.48(m, 1H), 7.77(m, 1H), 7.48-7.62(m, 4H), 7.12-7.28(m, 4H),.4.32(m, 1H), 4.08(m, 1H), 3.79(s, 2H), 2.63(t, J=7, 2H), 2.39(s, 3H),2.38(s, 3H), 1.80(m, 2H)

CDCl₃7.77(dd, J=8, 1, 1H), 7.57(d, J=8, 1H), 7.48-7.53(m, 2H), 7.46(d,J=8, 1H), 7.19(m, 1H), 7.14(d, J=8, 1H), 6.75-7.02(m, 2H), 4.31(m, 1H),4.07(m, 1H), 3.74(s, 2H), 2.60(t, J=7, 2H), 2.49(s, 3H), 2.38(s, 3H),2.37(s, 3H), 1.80(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.55(d, J=1, 1H), 7.47-7.51(m,2H), 7.18(m, 1H), 7.13(d, J=8, 1H), 7.00 (d, J=1, 1H), 4.23-4.33(m, 1H),4.04(m, 1H), 3.76 (S, 2H), 2.55(td, J=7, 3, 2H), 2.37(s, 3H), 2.36(s,3H), 1.64-1.80(m, 2H)

CDCl₃7.78-7.53(m, 1H), 7.57(d, J=8, 1H), 7.50-7.49(m, 2H), 7.19-7.15(m,1H), 7.12(d, J=8, 1H), 6.50-6.49(m, 1H), 6.07(d, J=2, 1H), 4.35-4.26(m,1H), 4.13-4.04(m, 1H), 3.76(s, 3H), 3.71(s, 2H), 2.54(t, J=7, 2H),2.39(s, 3H), 2.36(s, 3H), 1.76-1.63(m, 2H)

[0238] TABLE 22 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.80(dd, J=8, 2, 1H), 7.60(d, J=8, 1H), 7.55(m, 1H), 7.49(d, J=8,1H), 7.25(s, 1H), 7.21(m, 1H), 7.14(d, J=8, 1H), 4.40(m, 1H), 4.04(m,1H), 3.49(s, 2H), 2.45(m, 2H), 2.38(s, 3H), 2.37(s, 3H), 2.07(s, 3H),1.75(m, 2H)

CDCl₃8.39(d, J=2, 1H), 8.22(d, J=2, 1H), 7.77(d, J=8, 1H), 7.58(d, J=8,1H), 7.54-7.48(m, 2H), 7.19(m, 1H), 7.13(d, J=8, 1H), 4.32(m, 1H),4.10(m, 1H), 3.91(s, 2H), 2.61(m, 2H), 2.39(s, 3H), 2.36(s, 3H), 1.79(m,2H)

CDCl₃7.76(d, J=8, 1H), 7.69(m, 1H), 7.57(d, J=8, 1H), 7.51-7.47(m, 2H),7.18(m, 1H), 7.12(d, J=8, 1H), 6.94(s, 1H), 4.26(m, 1H), 4.25(q, J=7,2H), 4.07(m, 1H), 3.78(s, 3H), 3.74(d, J=2, 2H), 2.55(t, J=7, 2H),2.39(s, 3H), 2.36(s, 3H), 2.17(d, J=1, 3H), 1.70(m, 2H), 1.34(t, J=7,3H)

DMSO-d₆7.80(d, J=8, 1H), 7.76(d, J=8, 1H), 7.67(d, J=1, 1H),7.64-7.58(m, 2H), 7.38(s, 1H), 7.24(d, J=8, 1H), 7.20(d, J=8, 1H),4.50(m, 1H), 3.99(m, 1H), 3.99(s, 2H), 3.75(s, 3H), 2.88(m, 1H), 2.70(m,1H), 2.35(s, 3H), 2.34(s, 3H), 2.04(d, J=1, 3H), 1.74 (m, 2H)

CDCl₃7.99(s, 1H), 7.76(dd, J=8, 1, 1H), 7.56(d, J=8, 1H), 7.53-7.47(m,2H), 7.18(m, 1H), 7.13(d, J=8, 1H), 4.28(m, 1H), 4.05(m, 1H), 3.97(s,3H), 3.94(s, 3H), 3.51(s, 2H), 2.48(t, J=7, 2H), 2.38(s, 3H), 2.37(s,3H), 1.76(m, 2H)

CDCl₃7.75(d, J=8, 1H), 7.56(d, J=8, 1H), 7.53-7.47(m, 2H), 7.28(s, 1H),7.18(m, 1H), 7.13(d, J=8, 1H), 4.28(m, 1H), 4.08(m, 1H), 3.77(s, 3H),3.71(d, J=2, 2H), 2.52(t, J=7, 2H), 2.39(s, 3H), 2.37(s, 3H), 1.70(m,2H)

[0239] TABLE 20 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.72(m, 1H), 7.56(d, J=8, 1H), 7.44-7.38(m, 2H), 7.30-7.18(m, 5H),7.15(d, J=8, 1H), 4.22-4.00(m, 2H), 3.62(s, 2H), 2.52(t, J=7, 2H),2.36(s, 6H), 1.62-1.78(m, 2H)

CDCl₃7.72(m, 1H), 7.55(d, J=8, 1H), 7.44-7.38(m, 2H), 7.14(d, J=8, 1H),7.04(d, J=6, 1H), 6.77(d, J=6, 1H), 4.22-4.00(m, 2H), 3.76(s, 3H),3.70(s, 2H), 2.52(t, J=7, 2H), 2.36(s, 6H), 1.58-1.70(m, 2H)

CDCl₃7.61(d, J=8, 1H), 7.45-7.36(m, 2H), 7.30-7.18(m, 5H), 7.17-7.12(m,2H), 4.42(m, 1H), 4.05(m, 1H), 3.63(s, 2H), 2.55(t, J=7, 2H), 2.38(s,6H), 1.82-1.66(m, 2H)

CDCl₃7.61(d, J=8, 1H), 7.46(dd, J=8, 1, 1H), 7.40(t, J=8, 1H), 7.15(dd,J=8, 1, 1H), 7.13(d, J=8, 1H), 7.04(d, J=6, 1H), 6.77(d, J=6, 1H),4.43(m, 1H), 4.05(m, 1H), 3.77(s, 3H), 3.73(d, J=16, 1H), 3.69(d, J=16,1H), 2.55(m, 2H), 2.40(s, 3H), 2.38(s, 3H), 1.74-1.64(m, 2H)

CDCl₃7.69(d, J=8, 1H), 7.57(d, J=8, 1H), 7.47(d, J=2, 1H), 7.30-7.25(m,2H), 7.24-7.18(m, 3H), 7.16-7.14(m, 2H), 4.38-4.20(m, 1H), 4.10-4.03(m,1H), 3.62(s, 2H), 2.54(t, J=7, 2H), 2.36(s, 6H), 1.80-1.65(m, 2H)

CDCl₃7.68(d, J=8, 1H), 7.56(d, J=8, 1H), 7.47(d, J=2, 1H), 7.16-7.13(m,2H), 7.04(d, J=6, 1H), 7.78(d, J=6, 1H), 4.40-4.00(m, 2H), 3.77(s, 3H),3.74(d, J=14, 1H), 3.69(d, J=14, 1H), 2.54(t, J=7, 2H), 2.37(s, 6H),1.75‥1.59(m, 2H)

[0240] TABLE 24 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.55(d, J=8, 1H), 7.48-7.40(m, 2H), 7.30-7.18(m, 6H), 7.15(d, J=8,1H), 4.20-4.00(m, 2H), 3.64(s, 2H), 2.53(t, J=7, 2H), 2.36(s, 6H),1.76-1.64(m, 2H)

CDCl₃7.54(d, J=8, 1H), 7.47-7.42(m, 2H), 7.19(m, 1H), 7.14(d, J=8, 1H),7.04(d, J=6, 1H), 6.78(d, J=6, 1H), 4.18-4.00(m, 2H), 3.76(s, 3H),3.71(s, 2H), 2.52(t, J=7, 2H), 2.37(s, 3H), 2.36(s, 3H), 1.70-1.60(m,2H)

CDCl₃8.07(d, J=2, 1H), 7.72(dd, J=2, 8, 1H), 7.60(d, J=8, 1H), 7.53(d,J=8, 1H), 7.30-7.17(m, 6H), 4.42-4.33(m, 1H), 4.20-4.12(m, 1H), 3.61(s,2H), 2.54(t, J=7, 2H), 2.39(s, 3H), 2.37(s, 3H), 1.76-1.66(m, 2H)

CDCl₃8.06(d, J=2, 1H), 7.72(dd, J=2, 8, 1H), 7.59(d, J=8, 1H), 7.55(d,J=8, 1H), 7.20(d, J=8, 1H), 7.05(d, J=6, 1H), 6.78(d, J=6, 1H),4.41-4.31(m, 1H), 4.20-4.10(m, 1H), 3.77(s, 3H), 3.70(s, 2H), 2.54(t,J=7, 2H), 2.38(s, 3H), 2.38(s, 3H), 1.75-1.60(m, 2H)

CDCl₃7.85(d, J=8, 1H), 7.73(d, J=2, 1H), 7.58(d, J=8, 1H), 7.43(dd, J=2,8, 1H), 7.30-7.16(m, 6H), 4.27-4.09(m, 2H), 3.62(s, 2H), 2.53(t, J=7,2H), 2.38(s, 3H), 1.72-1.64(m, 2H)

CDCl₃7.74(dd, J=1, 8, 1H), 7.65(dd, J=8, 2, 1H), 7.61(d, J=8, 1H),7.54-7.50(m, 1H), 7.30-7.25(m, 2H), 7.23-7.18(m, 3H), 7.13(d, J=8, 1H),4.50-4.40(m, 1H), 4.15-4.00(m, 1H), 4.02(s, 3H), 3.64(s, 2H), 2.56(t,J=7, 2H), 2.39(s, 3H), 2.38(s, 3H), 1.85-1.72(m, 2H)

[0241] TABLE 25 Ex. no. ¹H-NMR(400MHz) δ

DMSO-d6 8.27(d, J=2, 1H), 8.17(dd, J=2, 8, 1H), 7.76(d, J=8, 1H),7.63(d, J=8, 1H), 7.34-7.24(m, 6H), 7.21(d, J=8, 1H), 4.55-4.32(m, 1H),4.10-3.94(m, 1H), 3.83(d, J=14, 1H), 3.78(d, J=14, 1H), 2.88-2.76(m,1H), 2.71-2.48(m, 1H), 2.36(s, 3H), 2.34(s, 3H), 1.80-1.64(m, 2H)

CDCl₃7.64(d, J=8, 1H), 7.49(d, J=8, 1H), 7.31(s, 1H), 7.24(d, J=2, 1H),7.11-7.05(m, 3H), 6.98(dd, J=1, 8, 1H), 4.30-4.20(m, 1H), 4.02-3.93(m,1H), 3.86-3.78(m, 2H), 3.59(s, 2H), 2.86(t, J=6, 2H), 2.44(t, J=7, 2H),2.30(s, 3H), 2.30(s, 3H), 1.72-1.62(m, 2H)

DMSO-d6 7.68(d, J=8, 1H), 7.59-7.57(m, 2H), 7.30-7.25(m, 2H),7.22-7.17(m, 4H), 7.10(dd, J=1, 8, 1H), 4.78-4.50(m, 1H), 4.40-4.32(m,1H), 4.10-3.90(m, 1H), 3.74-3.64(m, 2H), 3.52(s, 2H), 2.84(t, J=7, 2H),2.40(t, J=7, 2H), 2.37(s, 3H), 2.36(s, 3H), 1.64-1.44(m, 2H)

DMSO-d6 7.64(d, J=8, 1H), 7.56-7.50(m, 2H), 7.32-7.26(m, 1H), 7.15(d,J=7, 1H), 7.13-7.05(m, 2H), 6.98-6.93(m, 1H), 4.73-4.66(m, 1H),4.40-4.28(m, 1H), 4.02-3.92(m, 1H), 3.68-3.60(m, 2H), 3.50(s, 2H),2.80(t, J=7, 2H), 2.40-2.30(m, 2H), 2.32(s, 6H), 1.62-1.48(m, 2H)

DMSO-d6 7.65-7.57(m, 1H), 7.46(d, J=8, 1H), 7.46-7.39(m, 2H),7.32-7.14(m, 5H), 7.09(d, J=8, 1H), 3.90-3.62(m, 2H), 3.37(s, 2H),2.55-2.40(m, 2H), 2.33(s, 3H), 2.32(s, 3H), 1.76-1.62(m, 2H)

CDCl₃7.57(d, J=8, 2H), 7.31-7.26(m, 1H), 7.25-7.22(m, 1H), 7.22-7.14(m,5H), 3.63(s, 2H), 3.56-3.52(m, 2H), 2.44(t, J=7, 2H), 2.40(s, 3H),2.32(s, 3H), 1.48-1.38(m, 2H),

DMSO-d6 8.22(s, 1H), 7.81(d, J=8, 1H), 7.74(d, J=8, 1H), 7.56(d, J=8,1H), 7.21-7.05(m, 6H), 4.41-4.30(m, 1H), 4.13-4.00(m, 1H), 3.37(s, 2H),2.42-2.28(m, 2H), 2.36(s, 3H), 2.33(s, 3H), 1.64-1.45(m, 2H)

[0242] TABLE 26 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.75(dd, J=8, 2, 1H), 7.49-7.45(m, 2H), 7.29-7.13(m, 7H), 4.17(m,1H), 4.00(m, 1H), 3.89(s, 3H), 3.64(s, 2H), 2.52(t, J=7, 2H), 2.37(s,3H), 2.23(s, 3H), 1.78-1.62(m, 2H),

CDCl₃7.79-7.76(m, 1H), 7.52-7.51(m, 2H), 7.30-7.24(m, 2H), 7.23-7.18(m,3H), 7.16-7.12(m, 1H), 6.96(m, 1H), 4.45-4.37(m, 1H), 4.02-3.94(m, 1H),3.63(s, 2H), 2.74(s, 3H), 2.55(t, J=7, 2H), 2.34(s, 3H), 2.32(s, 3H),1.86-1.67(m, 2H)

CDCl₃7.76(dd, J=1, 7, 1H), 7.53-7.51(m, 2H), 7.15-7.11(m, 1H), 7.05 (d,J=6, 1H), 6.95(s, 1H), 6.77(d, J=6, 1H), 4.45-4.38(m, 1H), 4.04-3.95(m,1H), 3.77(s, 3H), 3.74(s, 2H), 2.73(s, 3H, 2.59-2.53(m, 2H), 2.35(s,3H), 2.32(s, 3H), 1.78-1.63(m, 2H)

CDCl₃7.78(dd, J=8, 2, 0.5H), 7.78(dd, J=8, 2, 0.5H), 7.58(d, J=8, 1H),7.44-7.55(m, 2H), 7.15(d, J=8, 1H), 7.08-7.22(m, 2H), 6.85(dd, J=8, 2,1H), 6.76(d, J=8, 1H), 6.72(t, J=8, 1H), 4.23-4.40(m, 1H), 4.06(dt,J=14, 7, 0.5H), 3.84(dt, J=14, 7, 0.5H), 3.67-3.74(m, 1H), 2.51-2.59(m,1H), 2.40(s, 3H), 2.36(s, 1.5H), 2.34(s, 1.5H), 2.32-2.44(m, 1H),1.65-1.85(m, 2H), 1.29(d, J=7, 1.5H), 1.23(d, J=7, 1.5H)

Example 103

[0243] 1,2-Dimethyl-10-[3-(4-morpholino)propyl]phenothiazine-5Oxide

[0244] 0.6 g of 1,2-dimethyl-10-(3-chloropropyl)phenothiazine-5-oxideobtained in Production Example 3, 260 ml of morpholine, a catalyticamount of triethylammonium iodide and 410 mg of potassium carbonate wereadded to 5 ml of N,N-dimethylformamide followed by stirring at 90° C.for 4 hr. Then the reaction mixture was cooled to room temperature.After adding water, the liquid reaction mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 430 mg of the title compound.

[0245]¹H-NMR, (400 MHz, CDCl₃) δ

[0246] 7.78 (m, 1H), 7.58 (d, J=8, 1H), 7.52-7.49 (m, 2H), 70.21-7.16(m, 1H), 7.13 (d, J=8, 1H), 4.26 (m, 1H), 4.08 (m, 1H), 3.57 (t, J=5,4H), 2.39 (s, 3H), 2.37 (s, 3H), 2.32-2.15 (m, 6H), 1.71 (m, 2H).

[0247] The following compounds were obtained by the same procedure asthe one of Example 103. TABLE 27 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.80(dd, J=8, 1, 1H), 7.59(m, 1H, 7.59(d, J=7, 1H), 7.52(dd, J=8,1, 1H), 7.23(m, 1H), 7.17(d, J=8, 1H), 4.54(m, 1H), 4.08-4.00(m, 1H),3.15-3.02(m, 1H), 2.90-2.50(m, 5H), 2.40(s, 3H), 2.39(s, 3H),2.20-2.10(m, 2H), 1.82-1.66(m, 4H), 1.55-1.40(m, 2H)

CDCDl₃7.78(dd, J=8, 1, 1H), 7.58(d, J=8, 1H), 7.51(m, 1H), 7.45(dd, J=8,1, 1H), 7.30-7.12(m, 7H), 4.28-4.19(m, 1H), 3.97(m, 1H), 3.48(d, J=14,1H), 3.42(d, J=14, 1H), 3.41-3.34(m, 2H), 2.52-2.40(m, 4H), 2.38(s, 3H),2.34(s, 3H), 1.74(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.58(d, J=8, 1H), 7.52-7.48(m, 2H), 7.18(m, 1H),7.13(d, J=8, 1H), 4.30-4.20(m, 1H), 4.05(m, 1H), 3.64-3.53(m, 1H),2.64-2.56(m, 1H), 2.54-2.46(m, 1H), 2.48(s, 3H), 2.37(s, 3H),2.30-2.20(m, 2H), 2.05-1.86(m, 2H), 1.83-1.67(m, 4H), 1.50-1.36(m, 2H)

CDCl₃7.78(d, J=8, 1H), 7.58(d, J=8, 1H), 7.54-7.47(m, 2H), 7.18(t, J=8,1H), 7.13(d, J=8, 1H), 4.30-4.20(m, 1H), 4.05(m, 1H), 2.83-2.77(m, 1H),2.73-2.67(m, 1H), 2.38(s, 3H), 2.38(s, 3H), 2.27(s, 6H), 2.41-2.23(m,2H), 2.14-2.04(m, 1H), 1.88-1.68(m, 6H), 1.50-1.36(m, 2H)

CDCl₃7.79(d, J=8, 1H), 7.59(d, J=8, 1H), 7.53-7.48(m, 2H), 7.18(m, 1H),7.14-7.03(m, 4H), 6.95-6.90(m, 1H), 4.36-4.26(m, 1H), 4.13(m, 1H),3.45(d, J=14, 1H), 3.35(d, J=14, 1H), 2.81-2.74(m, 2H), 2.37(m, 1H),2.51-2.35(m, 3H), 2.35(s, 3H), 1.85-1.71(m, 2H)

CDCl₃7.76-7.69(m, 1H), 7.56-7.41(m, 3H), 7.26-7.04(m, 7H), 4.40-4.25(m,1H), 4.00-3.70(m, 3H), 3.13-2.98(m, 2H), 2.42-2.25(m, 2H), 2.32(s, 3H),2.30(s, 3H), 1.95-1.75(m, 2H)

[0248] TABLE 28 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.78(d, J=8, 1H), 7.57(d, J=8, 1H), 7.48-7.55(m, 2H), 7.15-7.33(m,6H), 7.13(d, J=8, 1H), 4.35-4.48(m, 1H), 3.94-4.09(m, 1H), 3.87(d, J=14,0.5H), 3.86(d, J=14, 0.5H), 3.68(d, J=14, 0.5H), 3.63(d, J=14, 0.5H),3.25-3.33(m, 1H), 2.94-3.06(m, 1H), 2.82-2.91(m, 0.5H), 2.68-2.77(m,0.5H), 2.46-2.66(m, 4H), 2.38(s, 6H), 2.26-2.41(m, 2H), 1.76-1.97(m, 2H)

CDCl₃7.76(d, J=7, 0.5H), 7.74(d, J=7, 0.5H), 7.46-7.60(m, 3H), 7.26-7.39(m, 5H), 7.18(d, J=8, 1H), 7.13(d, J=8, 0.5H), 7.12(d, J=8, 0.5H),4.48-4.60(m, 1H), 4.04(s, 1H), 3.92-4.02(m, 1H), 2.50-3.20(m, 10H),2.38(s, 1.5H), 2.38(S, 1.5H), 2.35(s, 1.5H), 2.35(s, 1.5H), 2.12-2.24(m, 2H)

CDCl₃8.54(d, J=4, 1H), 7.77(d, J=8, 1H), 7.62(td, J=8, 2, 1H), 7.57(d,J=8, 1H), 7.46-7.54(m, 2H), 7.34(d, J=8, 1H), 7.10-7.21(m, 3H),4.22-4.34(m, 1H), 4.04(dt, J=14, 7, 1H), 3.61(s, 2H), 2.26-2.56(m, 10H),2.37(m, 2H), 2.37(s, 6H)

CDCl₃7.75(dd, J=8, 2, 1H), 7.58(td, J=8, 2, 1H), 7.53(d, J=7, 1H),7.47(d, J=8, 1H), 7.25(t, J=8, 2H), 7.19(t, J=7, 1H), 7.08(d, J=8, 1H),6.96(t, J=8, 1H), 6.81(d, J=8, 2H), 4.50(dt, J=14, 4, 1H), 4.03-4.18(m,3H), 3.02-3.08(m, 2H), 2.83(t, J=7, 2H), 2.40(s, 3H), 2.39(s, 3H),2.09-2.19(m, 2H)

CDCl₃7.78(d, J=8, 1H), 7.58(d, J=8, 1H), 7.48-7.51(m, 2H), 7.16-7.21(m,1H), 7.11-7.16(m, 1H), 7.13(d, J=8, 1H), 6.95(dd, J=8, 1, 1H) 6.78(dd,J=8, 1, 1H), 6.76(td, J=7, 1, 1H), 4.20-4.29(m, 1H), 4.03(dt, J=14, 7,1H), 3.64(s, 2H), 2.38(s, 6H), 2.20-2.38(m, 10H), 1.91(tt, J=7, 7, 2H)

CDCl₃7.75(dd, J=8, 2, 1H), 7.70-7.74(m, 2H), 7.50-7.62(m, 4H), 7.41-7.49(m, 2H), 7.16(ddd, J=8, 6, 2, 1H), 7.09(d, J=8, 1H), 4.18(dt, J=14, 7,1H), 3.97(dt, J=14, 7, 1H), 2.81-2.93(m, 4H), 2.15-2.37(m, 6H), 2.29(s,3H), 2.28(s, 3H), 1.60-1.70(m, 2H)

[0249] TABLE 29 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.79(d, J=8, 1H), 7.61(d, J=8, 1H), 7.46-7.56(m, 2H), 7.18(t, J=8,1H), 7.12(d, J=8, 1H), 6.69(t, J=8, 1H), 6.40-6.56(m, 3H), 4.46(dt,J=14, 7, 1H), 4.02(m, 2H), 2.86-2.98(m, 2H), 2.35(s, 6H), 1.88-1.99(m,1H), 1.76-1.88(m, 1H)

CDCl₃7.75(d, J=8, 1H), 7.56(d, J=8, 0.5H), 7.55(d, J=8, 0.5H),7.42-7.47(m, 2H), 7.28-7.35(m, 3H), 7.12-7.18(m, 3H), 7.10(d, J=8,0.5H), 7.09(d, J=8, 0.5H), 4.12-4.22(m, 1H), 3.88-4.03(m, 2H),3.57-3.65(m, 2H), 2.42-2.52(m, 2H), 2.14-2.39(m, 8H), 2.30(s, 3H),2.29(s, 1.5H), 2.28(s, 1.5H), 1.60-1.71(m, 2H)

CDCl₃7.83(d, J=8, 1H), 7.65(d, J=8, 1H), 7.53-7.59(m, 1H), 7.48(d, J=9,1H), 7.19-7.24(m, 1H), 7.17(d, J=8, 1H), 6.99(s, 1H), 4.29-4.38(m, 1H),4.10-4.19(m, 1H), 3.94-4.03(m, 2H), 3.76-3.88(m, 2H), 2.37(s, 3H),2.64(s, 3H), 2.09-2.20(m, 2H)

CDCl₃7.83(dd, J=8, 2, 1H), 7.61(d, J=8, 1H), 7.57-7.62(m, 1H), 7.50 (d,J=8, 1H), 7.34(s, 1H), 7.22(t, J=8, 1H), 7.15(d, J=8, 1H), 4.81-4.88(m,2H), 4.43-4.50(m, 1H), 3.94-4.03(m, 1H), 3.74-3.99(m, 2H), 2.38(s, 3H),2.33(s, 3H), 2.09-2.30(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.67(d, J=4, 1H), 7.57(d, J=8, 1H), 7.50(d, J=4,1H), 7.46-7.52(m, 1H), 7.15-7.23(m, 2H), 7.13(d, J=8, 1H), 4.27-4.38 (m,1H), 4.07-4.16(m, 1H), 3.96(s, 2H), 2.61(t, J=6, 2H), 2.40(s, 3H),2.37(s, 3H), 1.64-1.79(m, 2H)

DMSO-d6 7.65(d, J=8, 1H), 7.56(d, J=8, 2H), 7.42(t, J=8, 1H), 7.21(d,J=8, 1H), 7.17(d, J=7, 2H), 7.12(t, J=8, 1H), 7.01(d, J=7, 2H), 5.38(d,J=15, 1H), 5.23(d, J=15, 1H), 3.20-3.40(m, 2H), 2.55-2.68(m, 2H),2.45(s, 3H), 2.33(s, 3H), 2.05-2.17(m, 1H), 1.78-1.93(m, 2H),1.64-1.78(m, 2H), 1.38-1.52(m, 2H)

CDCl₃7.73(d, J=8, 1H), 7.63(d, J=8, 1H), 7.42(d, J=8, 1H), 7.29-7.36(m,6H), 7.22-7.29(m, 2H), 7.15(d, J=8, 1H), 7.14(d, J=8, 1H), 7.08(m, 1H),5.54(d, J=16, 1H), 5.37(d, J=16, 1H), 3.62(s, 2H), 3.52(s, 2H), 2.48(s,3H), 2.36(s, 3H), 2.40-2.60(m, 8H)

[0250] TABLE 30 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.79(d, J=8, 1H), 7.60(d, J=8, 1H), 7.55-7.45(m, 2H), 7.18(t, J=8,1H), 7.13(d, J=8, 1H), 7.08(t, J=8, 2H), 6.61(t, J=8, 1H), 6.40(d, J=8,2H), 4.35(m, 1H), 4.07(m, 1H), 3.80-3.63(m, 1H), 3.08-2.95(m, 2H),2.34(s, 3H), 2.33(s, 3H), 1.96-1.81(m, 2H)

CDCl₃7.75(d, J=8, 1H), 7.56-7.40(m, 4H), 7.36-7.21(m, 4H), 7.18(m, 1H),7.13(d, J=8, 1H), 4.39-4.20(m, 1H), 4.12-4.00(m, 1H), 2.75-2.56(m, 2H),2.56-2.30(m, 4H), 2.39(s, 3H), 2.38(s, 3H), 2.20-2.00(m, 2H),1.93-1.78(m, 2H), 1.70-1.55(m, 2H)

CDCl₃7.78(dd, J=8, 2, 1H), 7.58(d, J=8, 1H), 7.54(m, 1H), 7.49(dd, J=8,1, 1H), 7.33-7.16(m, 6H), 7.15(d, J=8, 1H), 4.31(dd, J=14, 7, 1H),4.05(dd, J=14, 7, 1H), 3.51(d, J=14, 1H), 3.47(d, J=14, 1H),2.64-2.50(m, 3H), 2.40(s, 3H), 2.38(s, 3H), 2.35(s, 6H), 2.50-2.31(m,3H), 1.84-1.69(m, 2H)

CDCl₃7.76(dd, J=8, 2, 1H), 7.57(d, J=8, 1H), 7.52-7.46(m, 2H), 7.19(m,1H), 7.13(d, J=8, 1H), 4.28(m, 1H), 4.05(m, 1H), 3.27(d, J=3, 2H),2.58(m, 1H), 2.38(s, 3H), 2.36(s, 3H), 2.12(t, J=3, 1H), 1.78-1.69(m,2H)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.51-7.46(m, 2H), 7.32-7.15(m,6H), 7.12(d, J=8, 1H), 4.28-4.19(m, 1H), 4.04(m, 1H), 3.45(s, 2H),2.46-2.18(m, 10H), 2.37(s, 3H), 2.36(s, 3H), 1.78-1.68(m, 2H)

CDCl₃7.80-7.75(m, 1H), 7.60(d, J=8, 0.5H), 7.59(d, J=8, 0.5H),7.57-7.46(m, 2H), 7.30-7.13(m, 6H), 7.05(dd, J=8, 2, 1H), 4.50-4.37(m,1H), 4.12-3.98(m, 1H), 3.63(dd, J=9, 4, 0.5H), 3.59-3.51(m, 1H),3.43-3.37(m, 1H), 3.35(dd, J=11, 9, 0.5H), 2.49-2.37(m, 1.5H), 2.42(s,1.5H), 2.41(s, 1.5H), 2.38(s, 3H), 2.33-2.25(m, 0.5H), 1.81-1.70(m, 2H)*: R configuration

DMSO-d6 7.77(dd, J=8, 1, 1H), 7.75(m, 1H), 7.73(d, J=8, 1H), 7.56(d,J=8, 1H), 7.20(t, J=8, 1H), 7.17(d, J=8, 1H), 4.40-4.30(m, 1H),4.15-4.00(m, 2H), 2.60-2.51(m, 1H), 2.34(s, 3H), 2.33(s, 3H),2.27-2.40(m, 1H), 2.21-2.11(m, 1H), 2.11-1.97(m, 2H), 1.77-1.17(m, 7H)

Example 130

[0251] 1,2-Dimethyl-10-(3-cyanomethylpropyl)phenothiazine-5-oxide

[0252] 2.25 g of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine-5-oxidesynthesized in Example 8, 990 mg of bromoacetonitrile and 1.2 g ofpotassium carbonate were dissolved in 50 ml of N,N-dimethylformamidefollowed by stirring at 80° C. for 10 min. Then the reaction mixture wascooled to room temperature and, after adding water, extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 670 mg of the title compound.

[0253]¹H-NMR,(400 MHz, CDCl₃) δ

[0254] 7.78 (m, 1H), 7.58 (d, =8, 1H), 7.52-7.49 (m, 2H), 7.21-7.16 (m,9H), 7.13 (d, J=8,1H), 4.36 (m, 1H), 4.08 (m, 1H), 3.39 (s, 2H), 2.61(t, J=7, 2H), 2.37 (s, 6H), 1.71 (m, 2H).

[0255] The following compounds were obtained by the same procedure asthe one of Example 130 or the same while changing the amount of thehalide. TABLE 31 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.80(dd, J=2, 8, 1H), 7.60(d, J=8.0, 1H), 7.59-7.54(m, 1H),7.51(dd, J=1.0, 8.0, 1H), 7.23-7.19(m, 1H), 7.16(d, J=8.0, 1H),4.45-4.38(m, 1H), 4.12-4.05(m, 1H), 3.41(d, J=17, 2H), 3.34(d, J=17,2H), 2.72-2.64(m, 1H), 2.58-2.51(m, 1H), 2.40(s, 3H), 2.39(s, 3H),1.90-1.80(m, 1H), 1.76-1.62(m, 1H)

DMSO-d6 7.74(d, J=8, 1H), 7.71(d, J=8, 1H), 7.56(m, 1H), 7.53(d, J=8,1H), 7.19(t, J=8, 1H), 7.15(d, J=8, 1H), 4.36-4.26(m, 1H), 4.03(m, 1H),2.96(s, 4H), 2.50-2.42(m, 2H), 2.32(s, 3H), 2.31(s, 3H), 1.46-1.35(m,2H)

DMSO-d6 7.78(d, J=8, 1H), 7.70(d, J=8, 1H), 7.61-7.55(m, 2H),7.27-7.16(m, 7H), 5.74(s, 1H), 3.99-3.88(m, 2H), 2.74-2.34(m, 2H),2.32(s, 1.5H), 2.31(s, 3H), 2.30(s, 1.5H), 1.76-1.65(m, 2H) (a mixtureof diastereomer and enantiomer)

[0256] The following compounds were synthesized by treating the compoundobtained by the same procedure as the one of Example 22 in the samemanner as the one of Example 130. TABLE 32 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.77-7.74(m, 1H), 7.55(d, J=8, 1H), 7.52-7.44(m, 2H), 7.22-7.14 (m,2H), 7.11(d, J=8, 1H), 6.93-6.88(m, 2H), 6.79-6.75(m, 1H), 4.30-4.19(m,1H), 4.14(q, J=7, 2H), 3.99-3.88(m, 1H), 3.64(s, 2H), 3.15(s, 2H),2.49(t, J=6, 2H), 3.99-3.88(m, 1H), 3.64(s, 2H), 3.15(s, 2H), 2.49(t,J=6, 2H), 2.36(s, 6H), 1.72-1.53(m, 2H), 1.23(t, J=7, 3H)

DMSO-d6 7.73(d, J=8, 1H), 7.62-7.59(m, 1H), 7.56-7.51(m, 2H), 7.21-7.14(m, 2H), 7.09-7.04(m, 1H), 6.91-6.89(m, 1H), 6.70-6.63(m, 2H),4.25-4.12(m, 1H), 3.99-3.76(m, 1H), 3.46(s, 2H), 2.89(s, 2H),2.40-2.28(m, 2H), 2.34(s, 3H), 2.26(s, 3H), 1.52-1.35(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.56(d, J=8, 1H), 7.44-7.53(m, 2H), 7.14-7.21 (m,2H), 7.11(d, J=8, 1H), 6.91(d, J=7, 1H), 6.85(d, J=8, 1H), 6.76(t, J=7,1H), 4.19-4.30(m, 1H), 3.87-3.96(m, 1H), 3.69(d, J=14, 1H), 3.61(d,J=14, 1H), 3.33-3.44(m, 2H), 3.27(s, 3H), 2.50-2.61(m, 2H), 2.46(t, J=7,2H), 2.36(s, 6H), 1.67-1.80(m, 2H)

CDCl₃7.79(dd, J=8, 2, 0.5H), 7.78(dd, J=8, 2, 0.5H), 7.53-7.62(m, 2H),7.49(t, J=8, 1H), 7.13-7.23(m, 3H), 6.90(d, J=8, 1H), 6.82(d, J=8, 1H),6.76(t, J=8, 1H), 4.33-4.43(m, 1H), 3.87-4.00(m, 1H), 3.76 (d, J=14,0.5H), 3.73(d, J=14, 0.5H), 3.61(d, J=14, 0.5H), 3.48 (d, J=14, 0.5H),3.36-3.45(m, 1.5H), 3.28-3.33(m, 0.5H), 3.13-3.24(m, 1H), 2.14-2.54(m,10H), 1.74-1.91(m, 2H)

Example 138

[0257] 1,2-Dimethyl-10-[4-benzylamino(2-butenyl)]phenothiazine-5-oxide

[0258] The procedure of Production Example 1 was repeated while using1,4-dibromo-2-butene instead of 1-chloro-3-iodopropane followed by theprocedure of Production Example 3. Then the procedure of Example 103 wasrepeated while using benzylamine instead of morpholine to give the titlecompound.

[0259]¹H-NMR,(400 MHz, CDCl₃) δ

[0260] 7.72 (d, J=8, 1H), 7.58-7.53 (m, 2H), 7.49 (d, J=8, 1H),7.33-7.23 (m, 5H), 7.20 (t, J=8, 1H), 7.16 (d, J=8, 1H), 5.68-5.63 (m,2H), 4.70 (dd, 14, 6, 1H), 4.48 (dd, J=14, 6, 1H) 3.63 (s, 2H), 3.13 (d,J=4, 2H), 2.41 (s, 3H), 2.39 (s, 3H).

Example 139

[0261] 1,2-Dimethyl-10-(3-benzylaminobutyl)phenothiazine-5-oxide

[0262] 60 mg of1,2-dimethyl-10-(4-benzylamino(2butenyl))phenothiazine-5-oxide obtainedin Example 138 was dissolved in 10 ml of methanol. Then a catalyticamount of 10% palladium carbon was added thereto and the resultingmixture was stirred under hydrogen atmosphere of 1 atm for 2 hr. Afterfiltering off the palladium carbon, the filtrate was concentrated andthe residue was purified by silica gel column chromatography to give 10mg of the title compound.

[0263]¹H-NMR, (400 MHz, CDCl₃) δ

[0264] 7.72 (d, J=8, 1H), 7.61-7.53 (m, 2H), 7.49 (d, J=8, 1H),7.38-7.25 (m,5H), 7.19 (t, J=8, 1H), 7.14 (d, J=8, 1H), 4.42-4.30 (m,1H), 3.95-3.86 (m, 1H),3.83 (d, J=12, 1H), 3.77 (d, J=12, 1H), 2.56 (t,J=7, 2H), 2.39 (s, 3H), 2.36 (s, 3H), 1.80-1.49 (m, 4H).

[0265] The following compounds were obtained by the same procedure asthat of Example 139 and Example 164 as will be described hereinbelow.TABLE 33 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.77(d, J=8, 1H), 7.58(d, J=8, 1H), 7.45-7.56(m, 2H), 7.19(t, J=8,1H), 7.08-7.15(m, 2H), 6.89(d, J=8, 1H), 6.76(d, J=8, 1H), 6.72(d, J=8,1H), 4.22-4.32(m, 1H), 3.90(dt, J=14, 7, 1H), 3.86(d, J=14, 1H), 3.81(d,J=14, 1H), 2.46(t, J=7, 2H), 2.37(s, 3H), 2.36(s, 3H), 1.52-1.69(m, 2H),1.34-1.52(m, 2H)

CDCl₃7.77(d, J=7, 1H), 7.57(d, J=8, 1H), 7.46-7.54(m, 1H), 7.46(d,J=7.1H), 7.10-7.21(m, 3H), 6.89(d, J=7, 1H), 6.78(d, J=8, 1H), 6.73(t,J=7, 1H), 4.15-4.25(m, 1H), 3.91(dt, J=14, 7, 1H), 3.57(s, 2H), 2.36(s,3H), 2.34(s, 3H), 2.29(t, J=7, 2H), 2.15(s, 3H), 1.36-1.60(m, 4H)

Example 142

[0266] 1,2-Dimethyl-10-(2-aminoethyl)phenothiazine-5-oxide

[0267] Starting with 1.95 g of1,2-dimethyl-10-(2-phthalimidoethyl)phenothiazine obtained in ProductionExample 7, the procedures of Production Example 4 and Example 8 wererepeated to give 1.24 g of the title compound.

[0268]¹H-NMR,(400 MHz, CDCl₃) δ

[0269] 7.81 (dd, J=8, 1, 1H), 7.58 (d, J=8, 1H), 7.56-7.49 (m, 2H), 7.20(m, 1H), 7.13 (d, J=8, 1H), 4.54 (m, 1H), 4.18-4.09 (m, 1H), 3.09-3.01(m, 1H), 2.75-2.50 (m, 2H), 2.79 (m, 1H), 2.38 (s, 3H), 2.36 (s, 3H).

Example 143

[0270] 1,2-Dimethyl-10-(2-benzylaminoethyl)phenothiazine-5-oxide

[0271] Starting with 600 mg of1,2-dimethyl-10-(2-aminoethyl)phenothiazine-5-oxide obtained in Example142, the procedure of Example 22 was repeated to give 755 mg of thetitle compound.

[0272]¹H-NMR,(400 MHz, CDCl₃) δ

[0273] 7.81 (dd, J=8, 1, 1H), 7.58 (d, J=8, 1H), 7.54-7.45 (m, 2H),7.22-7.11 (m, 7H), 4.50 (m, 1H), 4.35-4.25 (m, 1H), 3.59 (s, 2H), 2.92(m, 1H), 2.66 (m, 1H), 2.37 (s, 3H), 2.36 (s, 3H).

[0274] The following compounds were obtained by the same procedure asthe one of Example 143. TABLE 34 Ex. no. ¹H-NMR(400MHz) δ

DMSO-d6 7.85(dd, J=1, 8, 1H), 7.79(d, J=8, 1H), 7.64-7.59(m, 2H),7.25-7.20(m, 2H), 6.99-6.95(m, 1H), 6.80(dd, J=2, 8, 1H), 6.61-6.56 (m,2H), 4.62-4.55(m, 1H), 4.10-4.40(m, 1H), 3.49(d, J=15, 1H), 3.37(d,J=15, 1H), 2.75-2.62(m, 1H), 2.52-2.43(m, 1H), 2.36(s, 6H)

CDCl₃7.82(dd, J=1, 7, 1H), 7.60(d, J=8, 1H), 7.57-7.50(m, 2H),7.23-7.19(m, 1H), 7.17(d, J=8, 1H), 6.96(d, J=7, 1H), 6.66-6.57(m, 2H),4.52-4.47(m, 1H), 4.15-4.09(m, 1H), 3.78(d, J=15, 1H), 3.47(d, J=15,1H), 2.91-2.84(m, 1H), 2.58-2.54(m, 1H), 2.42(s, 3H), 2.39(s, 3H),2.16(s, 3H)

CDCl₃7.82(dd, J=2, 8, 1H), 7.62-7.56(m, 2H), 7.53-7.50(m, 1H),7.25-7.21(m, 1H), 7.18-7.16(m, 2H), 6.68(d, J=3; 1H), 4.58-4.50(m, 1H),4.15-4.06(m, 1H), 3.80(d, J=15, 1H), 3.42(d, J=15, 1H), 2.91-2.83(m,1H), 2.58-2.50(m, 1H), 2.42(s, 3H), 2.39(s, 3H)

CDCl₃7.82(dd, J=1, 8, 1H), 7.60(d, J=8, 1H), 7.58-7.52(m, 2H),7.23-7.19(m, 1H), 7.17(d, J=8, 1H), 7.04(dd, J=2, 7, 1H), 6.68-6.31 (m,2H), 4.52-4.45(m, 1H), 4.15‥4.08(m, 1H), 3.78(d, J=14, 1H), 3.49(d,J=14, 1H), 3.28-3.20(m, 1H), 2.91-2.84(m, 1H), 2.59-2.55(m, 1H), 2.42(s,3H), 2.39(s, 3H), 1.20(d, J=7, 3H), 1.17(d, J=7, 3H)

CDCl₃7.81(d, J=8, 1H), 7.59(d, J=8, 1H), 7.45-7.52(m, 2H), 7.18(m, 1H),7.12(d, J=8, 1H), 6.68(s, 2H), 4.45(m, 1H), 4.42(m, 1H), 3.42(d, J=15,1H), 3.39(d, J=15, 1H), 2.87(m, 1H), 2.59(m, 1H), 2.36(s, 3H), 2.35(s,3H), 2.08(s, 6H)

CDCl₃7.79(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.45-7.52(m, 2H), 7.17 (m,1H), 7.11(d, J=8, 1H), 6.37(s, 2H), 4.49(m, 1H), 4.16(m, 1H), 3.74(s,6H), 3.47(t, J=3, 2H), 2.91(m, 1H), 2.50(m, 1H), 2.35(s, 3H), 2.34(s,3H)

CDCl₃7.80(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.51-7.58(m, 2H), 7.20 (m,1H), 7.15(d, J=8, 1H), 6.87(t, J=8, 1H), 6.22(d, J=8, 2H), 4.49(m, 1H),4.18(m, 1H), 3.70(d, J=15, 1H), 3.60(d, J=15, 1H), 2.88(m, 1H), 2.64(m,1H), 2.39(s, 3H), 2.38(s, 3H)

[0275] TABLE 35 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.81(dd, J=2, 8, 1H), 7.60(d, J=8, 1H), 7.50-7.59(m, 2H),7.13-7.23(m, 3H), 6.74(dd, J=2, 8, 1H), 6.67(t, J=8, 1H), 4.49(m, 1H),4.45(s, 2H), 4.11(m, 1H), 3.79(d, J=15, 1H), 3.49(d, J=15, 1H), 3.39(s,3H), 2.88(m, 1H), 2.56(m, 1H), 2.42(s, 3H), 2.89(s, 3H)

CDCl₃7.82(dd, J=2, 8, 1H), 7.61(d, J=8, 1H), 7.51-7.59(m, 2H), 7.22 (dt,J=2, 8, 1H), 7.18(d, J=8, 1H), 7.03(dd, J=2, 8, 1H), 6.75 (d, J=8, 1H),6.65(t, J=8, 1H), 4.63(s, 2H), 4.50(m, 1H), 4.13 (m, 1H), 3.80(d, J=15,1H), 3.51(d, J=15, 1H), 2.80(m, 1H), 2.58(m, 1H), 2.43(s, 3H), 2.40(s,3H)

CDCl₃7.81(d, J=8, 1H), 7.60(d, J=8, 1H), 7.47-7.54(m, 2H), 7.18-7.23(m,1H), 7.13(d, J=8, 1H), 7.00(d, J=8, 1H), 6.68(d, J=8, 1H), 4.46-4.53(m,1H), 4.15-4.25(m, 1H), 3.60(d, J=14, 1H), 3.54(d, J=14, 1H),2.96-3.04(m, 1H), 2.60-2.68(m, 1H), 2.38(s, 3H), 2.37(s, 3H)

DMSO-d6 7.85(dd, J=1, 8, 1H), 7.78(d, J=8, 1H), 7.64-7.59(m, 2H),7.25-7.19(m, 2H), 6.72(dd, J=1, 8, 1H), 6.54(dd, J=8, 8, 1H), 6.41 (dd,J=1, 8, 1H), 4.64-4.55(m, 1H), 4.09-3.99(m, 1H), 3.66(s, 3H), 3.50(d,J=14, 1H), 3.37(d, J=14, 1H), 2.74-2.62(m, 1H), 2.52-2.43(m, 1H),2.36(S, 6H)

CDCl₃7.79(d, J=8, 1H), 7.58(d, J=8, 1H), 7.48-7.50(m, 2H), 7.16-7.26(m,1H), 7.12(d, J=8, 2H), 7.05(d, J=8, 1H), 6.79(t, J=8, 1H), 6.75(d, J=8,1H), 4.40(m, 1H), 4.20(m, 1H), 3.71(s, 3H), 3.62(d, J=17, 1H), 3.56(d,J=17, 1H), 2.90(m, 1H), 2.71(m, 1H), 2.36(s, 3H), 2.36(s, 3H)

CDCl₃7.81(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.49-7.58(m, 2H),7.14-7.24(m, 5H), 7.04(d, J=8, 1H), 4.52(d, J=12, 1H), 4.47(m, 1H),4.41(d, J=12, 1H), 4.02(m, 1H), 3.70(d, J=12, 1H), 3.43 (d, J=12, 1H),2.80(m, 1H), 2.50(m, 1H), 2.37(s, 3H), 2.34(s, 3H)

CDCl₃7.79(d, J=8, 1H), 7.57(d, J=8, 1H), 7.53(d, J=5, 2H), 7.10-7.20(m,3H), 6.93(dd, J=2, 8, 1H), 6.79-6.83(m, 2H), 4.45(m, 1H), 4.17(m, 1H),4.07-4.10(m, 2H), 3.55-3.58(m, 2H), 3.54(d, J=12, 1H), 3.41(d, J=12,1H), 2.88(m, 1H), 2.62(m, 1H), 2.36(s, 6H)

[0276] TABLE 36 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.81(d, J=8, 1H), 7.54-7.61(m, 2H), 7.51(d, J=8, 1H), 7.16-7.28(m,4H), 7.10(d, J=8, 1H), 7.03-7.09(m, 1H), 4.60(d, J=14, 1H), 4.06-4.42(m,3H), 3.60(d, J=12, 1H), 3.36(d, J=12, 1H), 2.95(t, J=12, 1H), 2.55(d,J=12, 1H), 2.40(s, 6H), 2.10(s, 3H)

CDCl₃7.83(dd, J=8, 1, 1H), 7.54-7.63(m, 2H), 7.53(d, J=8, 1H),7.16-7.28(m, 4H), 7.14(d, J=8, 1H), 7.07(d, J=8, 1H), 4.57-4.64(m, 1H),4.29-4.38(m, 1H), 4.25(d, J=14, 1H), 4.18(d, J=14, 1H), 3.74(d, J=13,1H), 3.45(d, J=13, 1H), 2.81-2.90(m, 1H), 2.55-2.61(m, 1H), 2.38(s, 3H),2.36(s, 3H)

CDCl₃8.27(s, 1H), 8.08(d, J=5, 1H), 7.82(d, J=8, 1H), 7.60(d, J=8, 1H),7.48-7.57(m, 2H), 7.18-7.24(m, 1H), 7.15(d, J=8, 1H), 7.01(d, J=5, 1H),5.10(s, 2H), 4.54(d, J=14, 1H), 4.20-4.29(m, 1H), 3.54-3.66(m, 2H),3.40(s, 3H), 2.96-3.05(m, 1H), 2.62-2.69(m, 1H), 2.39(s, 3H), 2.38(s,3H)

CDCl₃7.80(d, J=8, 1H), 7.53-7.60(m, 3H), 7.41(d, J=8, 1H), 7.21(ddd,J=8, 6, 2, 1H), 7.14-7.18(m, 1H), 7.14(d, J=8, 1H), 6.86-6.92(m, 2H),4.56(d, J=14, 1H), 4.18-4.26(m, 1H), 3.67(d, J=14, 1H), 3.50(d, J=14,1H), 2.89-2.97(m, 1H), 2.64(s, 3H), 2.47-2.54(m, 1H), 2.43(s, 3H),2.42(s, 3H)

DMSO-d6 7.87(dd, J=1, 8, 1H), 7.75(d, J=8, 1H), 7.65(d, J=8, 1H),7.63-7.58(m, 2H), 7.25-7.19(m, 2H), 6.78-6.68(m, 2H), 4.62-4.53(m, 1H),4.10-4.00(m, 1H), 3.38(s, 2H), 2.72-2.62(m, 1H), 2.52-2.46 (m, 1H),2.35(s, 6H)

CDCl₃7.82(dd, J=1, 8, 1H), 7.60-7.51(m, 3H), 7.34(d, J=7, 1H),7.26-7.20(m, 1H), 7.17(d, J=8, 1H), 6.94(d, J=8, 1H), 6.69(dd, J=8, 8,1H), 4.56-4.51(m, 1H), 4.16-4.09(m, 1H), 3.88(d, J=15, 1H), 3.50(d,J=15, 1H), 2.94-2.88(m, 1H), 2.59-2.54(m, 1H), 2.43(s, 3H), 2.40(s, 3H)

Example 164

[0277]1,2-Dimethyl-10-[3-[N-[(2-hydroxyphenyl)methyl]methylamino]propyl]phenothiazine

[0278] To 144 mg of1,2-dimethyl-10-[3-[N-(2-hydroxyphenyl)methylamino]propyl]phenothiazine-5-oxideobtained by the same procedure as that of Example 22 were added 1 mlportions of formic acid and a 37% solution of formaldehyde followed bystirred under reflux for 3.5 hr. After adding water, the reactionmixture was basified by adding a saturated aqueous solution of sodiumbicarbonate. Then it was extracted with methylene chloride and theorganic layer was washed with a saturated aqueous solution and driedover sodium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 120 mg of the title compound.

[0279]¹H-NMR,(400 MHz, CDCl₃) δ

[0280] 7.79-7.77 (m, 1H), 7.57 (d, J=8, 1H), 7.52-7.50 (m, 2H),7.21-7.12 (m,3H), 6.89 (dd, J=1, 8, 1H), 6.81 (dd, J 1, 8, 1H),6.77-6.73 (m, 1H),4.35-4.23 (m, 1H), 4.02-3.94 (m, 1H), 3.59 (d, J=14,1H), 3.51 (d, J=14, 1H), 2.46-2.34 (m, 2H), 2.39 (s, 3H), 2.37 (s, 3H),2.11 (s, 3H), 1.84-1.75 (m, 2H).

[0281] The following compounds were obtained by the same procedure asthat of Example 164. TABLE 37 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.77(dd, J=2, 8, 1H), 7.57(d, J=8, 1H), 7.52-7.56(m, 2H),7.19-7.13(m, 1H), 7.12(d, J=8, 1H), 6.92(d, J=8, 1H), 6.62(d, J=8, 2H),4.29-4.20(m, 1H), 4.06-3.97(m, 1H), 3.21(s, 2H), 2.36(s, 6H),2.33-2.19(m, 2H), 1.98(s, 3H), 1.80-1.77(m, 2H)

CDCl₃7.77(dd, J=1, 8, 1H), 7.58(d, J=8, 1H), 7.52-7.47(m, 2H),7.19-7.15(m, 1H), 7.12(d, J=8, 1H), 7.09-7.05(m, 1H), 6.65-6.62(m, 3H),4.31-4.22(m, 1H), 4.02-3.94(m, 1H), 3.27(s, 2H), 2.37(s, 6H),2.33-2.19(m, 2H), 2.08(s, 3H), 1.84-1.70(m, 2H)

CDCl₃7.78(d, J=8, 1H), 7.57(d, J=8, 1H), 7.51(m, 2H), 7.23(dd, J=8, 2,1H), 7.18(m, 1H), 7.12(d, J=8, 1H), 6.78(d, J=8, 1H), 6.67(t, J=8, 1H),4.33(m, 1H), 4.00(m, 1H), 3.59(d, J=14, 1H), 3.51(d, J=14, 1H),2.52-2.40(m, 2H), 2.40(s, 3H), 2.38(s, 3H), 2.12(s, 3H), 1.80-1.60(m,2H)

CDCl₃7.79-7.77(m, 1H), 7.57(d, J=8, 1H), 7.52-7.50(m, 2H), 7.21-7.17 (m,12H), 7.13(d, J=8, 1H), 7.03(dd, J=1, 8, 1H), 6.74(dd, J=1, 8, 1H),6.66(dd, J=7, 7, 1H), 4.35-4.24(m, 1H), 4.04-3.95(m, 1H), 3.56(d, J=14,1H), 3.48(d, J=14, 1H), 2.49-2.32(m, 2H), 2.40(s, 3H), 2.37(s, 3H),2.24(s, 3H), 2.24(s, 3H), 2.10(s, 3H), 1.85-1.76 (m, 2H)

CDCl₃7.77(dd, J=1, 8, 1H), 7.57(d, J=8, 1H), 7.48-7.44(m, 2H),7.20-7.16(m, 1H), 7.13(d, J=8, 1H), 6.81(dd, J=1, 8, 1H), 6.72(dd, J=8,8, 1H), 6.53(dd, J=1, 8, 1H), 4.40-4.25(m, 1H), 4.07-3.91 (m, 1H),3.90(s, 3H), 3.59(d, J=14, 1H), 3.52(d, J=14, 1H), 2.45-2.36(m, 2H),2.39(s, 3H), 2.36(s, 3H), 2.11(s, 3H), 1.88-1.74(s, 3H)

CDCl₃7.76(dd, J=2, 8, 1H), 7.57(d, J=8, 1H), 7.52-7.44(m, 2H),7.20-7.16(m, 2H), 7.13(d, J=8, 1H), 6.51(d, J=8, 2H), 4.25-4.16(m, 1H),4.03-3.94(m, 1H), 3.74(s, 6H), 3.47(d, J=14, 1H), 3.40(d, J=14, 1H),2.40-2.29(m, 2H), 2.35(s, 6H), 2.07(s, 3H), 1.88-1.67 (m, 2H)

CDCl₃7.77(dd, J=2, 8, 1H), 7.56(d, J=8, 1H), 7.54-7.47(m, 2H),7.21-7.16(m, 1H), 7.13(d, J=8, 1H), 6.65(d, J=8, 1H), 6.64-6.60(m, 1H),6.38(d, J=1, 1H), 4.32-4.20(m, 1H), 4.00-3.91(m, 1H), 3.48 (d, J=14,1H), 3.40(d, J=14, 1H), 2.42-2.33(m, 2H), 2.38(s, 3H), 2.37(s, 3H),2.10(s, 3H), 1.82-1.73(m, 2H)

[0282] TABLE 38 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.79(dd, J=1, 8, 1H), 7.57(d, J=8, 1H), 7.55-7.48(m, 2H),7.23-7.18(m, 2H), 7.13(d, J=8, 1H), 6.76(d, J=2, 1H), 4.39-4.37(m, 1H),4.03-3.95(m, 1H), 3.54(d, J=14, 1H), 3.46(d, J=14, 1H), 2.53-2.34(m,2H), 2.40(s, 3H), 2.38(s, 3H), 2.11(s, 3H), 1.90-1.75(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.48-7.52(m, 2H), 7.16-7.24(m,2H), 7.13(d, J=8, 1H), 7.04(d, J=8, 1H), 6.83-6.90(m, 2H), 4.27(m, 1H),4.16(t, J=4, 2H), 3.97(m, 1H), 3.51-3.53(m, 2H), 3.45(m, 1H), 3.32(m,1H), 2.30-2.48(m, 2H), 2.36(s, 6H), 2.04(s, 3H), 1.77-1.93(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.55(d, J=8, 1H), 7.43-7.53(m, 2H), 7.17(t, J=8,1H), 7.11(d, J=8, 1H), 6.80(d, J=8, 1H), 6.19(d, J=8, 1H), 4.27(m, 1H),3.95(m, 1H), 3.65(d, J=14, 1H), 3.60(d, J=14, 1H), 2.35-2.46(m, 2H),2.37(s, 3H), 2.36(s, 3H), 2.16(s, 3H), 2.12(s, 3H), 1.74-1.85(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.56(d, J=8, 1H), 7.46-7.53(m, 2H), 7.15-7.20(m,1H), 7.12(d, J=8, 1H), 6.57(s, 1H), 4.26(m, 1H), 3.98 (m, 1H), 3.80(s,3H), 3.68(d, J=14, 1H), 3.62(d, J=14, 1H), 3H), 1.71-1.85(m, 2H)

CDCl₃7.77(d, J=8, 1H), 7.57(d, J=8, 1H), 7.47-7.54(m, 2H), 7.18 (ddd,J=8, 6, 2, 1H), 7.13(d, J=8, 1H), 5.95(d, J=3, 1H), 5.02 (d, J=3, 1H),4.20-4.30(m, 1H), 3.99-4.07(m, 1H), 3.81(s, 3H), 3.29(d, J=14, 1H),3.22(d, J=14, 1H), 2.38(s, 3H), 2.37(S, 3H), 2.21-2.35(m, 2H), 2.08(s,3H), 1.62-1.79(m, 2H)

CDCl₃7.75(d, J=7, 1H), 7.56(d, J=8, 1H), 7.44-7.53(m, 2H), 7.18(t, J=7,1H), 7.13(d, J=8, 1H), 6.12(d, J=3, 1H), 5.95(d, J=3, 1H), 4.50(s, 2H),4.14-4.24(m, 1H), 4.02(m, 1H), 3.39(d, J=14, 1H), 3.32(d, J=14, 1H),2.36(s, 6H), 2.19-2.34(m, 2H), 2.12(s, 3H), 1.63-1.75(m, 2H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.46-7.54(m, 2H), 7.17 (ddd,J=8, 6, 2, 1H), 7.12(d, J=8, 1H), 7.10(d, J=5, 1H), 6.79(d, J=5, 1H),4.22-4.32(m, 1H), 4.06(ddd, J=14, 9, 6, 1H), 3.76(s, 3H), 3.50(d, J=14,1H), 3.44(d, J=14, 1H), 2.39(s, 3H), 2.36(s, 3H), 2.23-2.37(m, 2H),2.08(s, 3H), 1.63-1.80(m, 2H)

[0283] TABLE 39 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.76(dd, J=1, 8, 1H), 7.57(d, J=8, 1H), 7.46-7.42(m, 2H),7.20-7.13(m, 3H), 6.87-6.83(m, 2H), 6.76-6.72(m, 1H), 4.43-4.32(m, 1H),4.25-4.06(m, 1H), 3.63(s, 2H), 2.75-2.66(m, 1H), 2.62-2.53 (m, 1H),2.35(s, 3H), 2.31(s, 3H), 2.25(s, 3H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.48-7.46(m, 2H), 7.20-7.13(m,2H), 6.82(dd, J=1, 8, 1H), 6.71(dd, J=8, 1, 1H), 6.50 (dd, J=1, 8, 1H),4.46-4.37(m, 1H), 4.26-4.07(m, 1H), 3.90(s, 3H), 3.64(s, 2H),2.78-2.67(m, 1H), 2.65-2.56(m, 1H), 2.35(s, 3H), 2.32(s, 3H), 2.49(s,3H)

CDCl₃7.76(dd, J=2, 8, 1H), 7.57(d, J=8, 1H), 7.49-7.42(m, 2H),7.20-7.17(m, 1H), 7.14(d, J=8, 1H), 7.05-7.03(m, 1H), 6.73-6.64 (m, 2H),4.42-4.31(m, 1H), 4.19-4.08(m, 1H), 3.61(s, 2H), 2.72-2.55(m, 2H),2.35(s, 3H), 2.32(s, 3H), 2.25(s, 3H), 2.23(s, 3H)

CDCl₃7.77(d, J=8, 1H), 7.58(d, J=8, 1H), 7.43-7.46(m, 2H), 7.15-7.22(m,2H), 7.14(d, J=8, 1H), 7.09(d, J=8, 1H), 6.85(t, J=8, 1H), 6.81(d, J=8,1H), 4.22(m, 1H), 4.07(m, 1H), 3.74(s, 3H), 3.41(s, 2H), 2.58(m, 1H),2.49(m, 1H), 2.34(s, 3H), 2.32(s, 3H), 2.14(s, 3H)

CDCl₃7.76(d, J=8, 1H), 7.57(d, J=8, 1H), 7.47(m, 1H), 7.40(d, J=8, 1H),7.35(d, J=8, 1H), 7.29(d, J=8, 1H), 7.12-7.20(m, 3H), 7.07(d, J=8, 1H),4.61(d, J=12, 1H), 4.58(d, J=12, 1H), 4.26 (m, 1H), 3.97(m, 1H), 3.53(d,J=12, 1H), 3.50(d, J=12, 1H), 2.68(m, 1H), 2.58(m, 1H), 2.34(s, 3H),2.24(s, 3H), 2.17(s, 3H)

[0284] TABLE 40 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.76(d, J=8, 1H), 7.58(d, J=8, 1H), 7.43-7.50(m, 2H), 7.11-7.21(m,3H), 6.82(dd, J=1, 8, 1H), 6.72(t, J=8, 1H), 4.70(s, 2H), 4.39(m, 1H),4.12(m, 1H), 3.63(s, 2H), 2.71(m, 1H), 2.61(m, 1H), 2.36(s, 3H), 2.34(s,3H), 2.23(s, 3H)

CDCl₃7.70(d, J=8, 1H), 7.56(d, J=8, 1H), 7.48(d, J=2, 1H), 7.18-7.14(m,3H), 6.89(dd, J=2, 8, 1H), 6.81(dd, J=1, 8, 1H), 6.77-6.73(m, 1H),4.31-4.18(m, 1H), 4.03-3.96(m, 1H), 3.58(d, J=14, 1H), 3.51(d, J=14,1H), 2.49-2.36(m, 2H), 2.382(s, 3H), 2.379 (s, 3H), 2.12(s, 3H),1.84-1.75(m, 2H)

CDCl₃7.89(d, J=8, 1H), 7.71(s, 1H), 7.58(d, J=8, 1H), 7.43(d, J=8, 1H),7.18(d, J=8, 1H), 7.18-7.14(m, 1H), 6.89(d, J=8, 1H), 6.80(d, J=8, 1H),6.77-6.73(m, 1H), 4.32-3.29(m, 1H), 4.08-4.01 (m, 1H), 3.58(d, J=14,1H), 3.52(d, J=14, 1H), 2.47-2.35(m, 2H), 2.40(s, 3H), 2.39(s, 3H),2.12(s, 3H), 1.82-1.73(m, 2H)

CDCl₃7.65(d, J=8, 1H), 7.56(d, J=8, 1H), 7.32(s, 1H), 7.18-7.14(m, 1H),7.11(d, J=8, 1H), 6.99(dd, J=1, 8, 1H), 6.89(dd, J=2, 8, 1H), 6.82(dd,J=1, 8, 1H), 6.77-6.73(m, 1H), 4.35-4.25(m, 1H), 4.00-3.92(m, 1H),3.59(d, J=14, 1H), 3.50(d, J=14, 1H), 2.46-2.35(m, 2H), 2.42(s, 3H),2.38(s, 3H), 2.37(s, 3H), 2.10(s, 3H), 1.85-1.76(m, 2H)

CDCl₃7.68(d, J=8, 1H), 7.56(d, J=8, 1H), 7.18-7.14(m, 1H), 7.11(d, J=8,1H), 6.98(d, J=2, 1H), 6.90(d, J=7, 1H), 7.81(d, J=8, 1H), 6.77-6.72(m,2H), 4.36-4.28(m, 1H), 3.99-3.90(m, 1H), 3.86 (s, 3H), 3.62(d, J=14,1H), 3.50(d, J=14, 1H), 2.5-2.39(m, 2H), 2.39(s, 3H), 2.37(s, 3H),2.12(s, 3H), 1.89-1.77(m, 2H)

CDCl₃8.31(s, 1H), 7.98-7.91(m, 1H), 7.89(d, J=8, 1H), 7.59(d, J=8, 1H),7.28-7.12(m, 6H), 4.42(s, 3H), 4.42-4.22(m, 1H), 4.18-4.05 (m, 1H),3.38-3.25(m, 2H), 2.40(s, 3H), 2.38(s, 3H), 2.38-2.20 (m, 2H), 2.00(s,3H), 1.82-1.64(m, 2H)

Example 191

[0285]1,2-Dimethyl-10-[2-(4-benzylpiperazin-1-yl)ethyl]-phenothiazine-5-oxide

[0286] Starting with 1,2-dimethyl-10-(2-bromoethyl)phenothiazineobtained by Production Example 8, the procedures of Production Example 3and Example 103 were repeated to thereby synthesize the title compound.

[0287]¹H-NMR,(400 MHz, CDCl₃) δ

[0288] 7.78 (d, J=8, 1H), 7.59 (d, J=8, 1H), 7.41-7.48 (m, 2H),7.17-7.31 (m, 6H), 7.14 (d, J=8, 1H), 4.01-4.18 (m, 2H), 3.42 (s, 2H),2.36 (s, 3H), 2.34 (s, 3H), 2.20-2.51 (m, 10H).

[0289] The following compounds were obtained by the same procedure asthat of Example 191. Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.76(d, J=8, 1H), 7.58(d, J=8, 1H), 7.44-7.53(m, 2H), 7.38-7.44(m,2H), 7.30-7.37(m, 2H), 7.18-7.28(m, 2H), 7.15(d, J=8, 1H), 4.22-4.34(m,1H), 4.07-4.22(m, 1H), 2.43-2.65(m, 6H), 2.40(s, 3H), 2.35(s, 3H),1.85-1.99(m, 2H), 1.52-1.63(m, 2H)

CDCl₃7.76(dd, J=8, 2, 1H), 7.57(d, J=8, 1H), 7.42(m, 1H), 7.28(d, J=8,1H), 7.21-7.25(m, 3H), 7.15-7.19(m, 3H), 7.12(d, J=8, 1H), 4.15(dt,J=14, 7, 1H), 3.87(dt, J=14, 7, 1H), 3.51(s, 2H), 3.41(t, J=5, 2H),2.69(t, J=7, 2H), 2.57(t, J=5, 2H), 2.33(s, 3H), 2.20(s, 3H)

CDCl₃7.83(d, J=8, 1H), 7.60(d, J=8, 1H), 7.51-7.59(m, 2H), 7.21(m, 1H),7.10(d, J=8, 1H), 6.68(td, J=8, 2, 1H), 6.61(dd, J=8, 2, 1H),6.45-6.52(m, 2H), 4.84-4.92(m, 1H), 4.55(dt, J=14, 3, 1H), 4.38(m, 1H),3.42-3.52(m, 1H), 3.30-3.40(m, 1H), 2.32(s, 3H), 2.29(s, 3H)

CDCl₃7.85(d, J=8, 1H), 7.74(d, J=8, 1H), 7.63(d, J=8, 1H), 7.55-7.61(m,2H), 7.13-7.27(m, 5H), 4.52-4.61(m, 1H), 3.96-4.09(m, 1H), 3.36-3.47(m,1H), 3.26-3.36(m, 1H), 2.67-2.76(m, 1H), 2.40-2.50(m, 1H), 2.34(s, 6H)

Example 196

[0290] 1,2-Dimethyl-10-(3-aminopropyl)phenothiazine-5,5-dioxide

[0291] To 20 ml of a solution of 870 mg of1,2-dimethyl-10-(3-aminopropyl)phenothiazine obtained in Example 1 inmethanol was added an aqueous solution of 3.7 g of oxone in 20 ml ofwater and the resulting mixture was stirred at room temperature for 30min. After evaporating the solvent, the residue was purified by silicagel column chromatography to give 200 mg of the title compound.

[0292]¹H-NMR,(400 MHz, CDCl₃) δ

[0293] 7.96 (dd, J 8, 1, 1H), 7.79 (d, J=8, 1H), 7.57-7.53 (m, 1H), 7.46(d, J=8, 1H), 7.24-7.20 (m, 1H), 7.17 (d, J=8, 1H), 4.15-4.10 (m, 2H),2.61 (t, J=7, 2H), 2.38 (s, 6H), 1.70-1.60 (m, 2H).

[0294] The following compounds were obtained by subjecting the compoundsobtained in Examples 1, 4, 8, 22 and 103 to the same procedures as thoseof Examples 196 and Production Example 3. TABLE 42 Ex. no.¹H-NMR(400MHz) δ

CDCl₃7.74(d, J=8, 1H), 7.71(d, J=8, 1H), 7.55(dd, J=1, 1H), 7.28(dd,J=2, 8, 1H), 7.12(d, J=8, 1H), 4.01-4.06(m, 2H), 2.50-2.60(m, 2H),2.31(s, 3H), 2.29(s, 3H), 1.62-1.56(m, 2H)

CDCl₃7.97(dd, J=8, 2, 1H), 7.80(d, J=8, 1H), 7.55(m, 1H), 7.47(d, J=8,1H), 7.22(dd, J=8, 7, 1H), 7.17(d, J=8, 1H), 4.10-4.18(m, 2H),3.55-3.62(m, 4H), 2.38(s, 6H), 2.19-2.27(m, 6H), 1.65-1.74(m, 2H)

CDCl₃7.97(dd, J=8, 1, 1H), 7.80(d, J=8, 1H), 7.53-7.58(m, 1H),7.44-7.46(m, 1H), 7.31-7.41(m, 5H), 7.21-7.26(m, 1H), 7.19(d, J=8, 1H),4.16-4.25(m, 2H), 2.63-2.70(m, 2H), 2.53(t, J=7, 2H), 2.38-2.46(m, 2H),2.40(s, 3H), 2.38(s, 3H) 1.90-2.01(m, 2H), 1.60-1.67(m, 2H)

CDCl₃8.00(dd, J=8, 2, 1H), 7.79(d, J=8, 1H), 7.56-7.51(m, 1H), 7.45(d,J=8, 1H), 7.37(m, 1H), 7.30-7.25(m, 1H), 7.23-7.19(m, 4H), 7.16(d, J=8,1H), 4.28-4.10(m, 2H), 3.63(s, 2H), 2.53(t, J=7, 2H), 2.37(s, 3H),2.36(s, 3H), 1.73-1.68(m, 2H)

CDCl₃7.88(d, J=8, 1H), 7.78(d, J=8, 1H), 7.34(s, 1H), 7.30-7.18(m, 5H),7.15(d, J=8, 1H), 7.07(dd, J=8, 2, 1H), 4.18-4.08(m, 2H), 3.87(t, J=6,2H), 3.64(s, 2H), 2.91(t, J=6, 2H), 2.53(t, J=7, 2H), 2.36(s, 3H),2.35(s, 3H), 1.75-1.65(m, 2H)

CDCl₃7.96(dd, J=8, 2, 1H), 7.80(d, J=8, 1H), 7.54(m, 1H), 7.41(d, J=8,1H). 7.30-7.14(m, 7H), 4.04(m, 2H), 3.46(s, 2H), 3.44(t, J=6, 2H),2.50(t, J=6, 2H), 2.42(t, J=7, 2H), 2.38(s, 3H), 2.32(s, 3H), 1.70(m,2H)

Example 203

[0295] 3,4-Dimethyl-9-methylene-10-(3-aminopropyl)acridan

[0296] Starting with 154 mg of3,4-dimethyl-9-methylene-10-(3-bromopropyl)acridan obtained byProduction Example 9, the procedures of Production Example 2 and Example1 were repeated to thereby give 87 mg of the title compound.

[0297]¹H-NMR,(400 MHz, CDCl₃) δ

[0298] 7.52 (dd, J=8, 1, 1H), 7.31 (d, J=7, 1H), 7, 24 (dd, J=7, 1, 1H),7.21 (m, 1H), 7.01 (m, 1H), 6.92 (d, J=7, 1H), 5.36 (s, 1H), 5.28 (s,1H), 3.85 (t, J=7, 2H), 2.46 (t, J=7, 2H), 2.30 (s, 3H), 2.28 (s, 3H),1.54-1.43 (m, 2H).

[0299] The following compounds were obtained by the same procedure asthat of Example 203. TABLE 43 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃7.42-7.33(m, 1H), 7.29-7.12(m, 3H), 7.04-6.89(m, 2H), 5.90(m,0.5H), 5.80(m, 0.5H), 3.83(t, J=7, 1H), 3.66-3.58(m, 1H), 2.52-2.44(m,2H), 2.30(s, 6H), 2.10(d, J=7, 1.5H), 2.06(d, J=7, 1.5H), 1.52-1.42(m,2H) [a mixture of E- and Z- (1:1)]

CDCl₃7.35(d, J=8; 1H), 7.21(d, J=4, 1H), 7.16(t, J=8, 1H), 7.14(d, J=8,1H), 7.03-6.97(m, 1H), 6.95(d, J=8, 0.5H), 6.90(d, J=8, 0.5H), 5.76(t,J=7, 0.5H), 5.66(t, J=7, 0.5H), 3.83(t, J=7, 2H), 2.50(m, 2H), 2.45(m,2H), 2.30(s, 1.5H), 2.28(s, 3H), 2.26(s, 1.5H), 1.58-1.47(m, 4H),0.93(m, 3H) [a mixture of E- and Z- (1:1)]

Example 206

[0300] 3,4-Dimethyl-9-methylene-10-(3-benzylaminopropyl)acridan

[0301] Starting with 100 mg of3,4-dimethyl-9-methylene-10-(3-aminopropyl)acridan obtained by Example203, the procedure of Example 22 was repeated to thereby give 45 mg ofthe title compound.

[0302]¹H-NMR,(400 MHz, CDCl₃) δ

[0303] 7.53 (dd, J=8, 1, 1H), 7.32 (d, J=8, 1H), 7.28-7.17 (m, 5H),7.13-7.09 (m, 2H), 7.01 (m, 1H), 6.93 (d, J=8, 1H), 5.35 (s, 1H), 5.25(s, 1H), 3.87 (t, J=7, 2H), 3.50 (s, 2H), 2.36 (t, J=7, 2H), 2.30 (s,3H), 2.28 (s, 3H), 1.48 (m, 2H).

[0304] The following compounds were obtained by the same procedure asthat of Example 206. TABLE 44 Ex. no. ¹H-NMR(400MHz)

CDCl₃7.36(dd, J=8, 1, 0.5H), 7.35(d, J=8, 0.5H), 7.28-7.09(m, 8H),7.03-6.97(m, 1H), 6.95(d, J=8, 0.5H), 6.92(d, J=8, 0.5H), 5.74(t, J=7,0.5H), 5.64(t, J=7, 0.5H), 3.85(t, J=7, 2H), 3.51(s, 2H), 2.50(m, 1H),2.45(m, 1H), 2.41(t, J=7, 2H), 2.30(s, 1.5H), 2.29(s, 1.5H), 2.28(s,1.5H), 2.27(s, 1.5H), 1.61-1.46(m, 4H), 0.94(m, 3H)

Example 208

[0305] (E,Z)-3,4-Dimethyl-10-(3-aminopropyl)-9-acridoneoxime-O-methylEther

[0306] 1 ml of hydrazine hydrate was added to a mixture of 480 mg of(E,Z)-3,4-dimethyl-10-(3-phthalimidopropyl)-9-acridoneoxime-O-methylether with 50 ml of methanol followed by stirring at room temperaturefor 1 hr. After evaporating the major part of methanol under reducedpressure, water was added to the residue followed by extraction withethyl acetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 260 mg of the title compound as a mixture of the E- andZ-enantiomers (1:1).

[0307]¹H-NMR,(400 MHz, CDCl₃) δ

[0308] 8.42 (dd, J=8, 2, 0.5H), 8.32 (d, J=8, 0.5H), 7.80 (dd, J=8, 2,0.5H), 7.61 (d, J=8, 0.5H), 7.39-6.96 (m, 4H), 4.06 (s, 1.5H), 4.05 (s,1.5H), 4.00-3.90 (m, 2H), 2.41 (t, J=7, 2H), 2.34 (s, 1.5H), 2.33 (s,1.5H), 2.32 (s, 1.5H), 2.31 (s, 1.5H), 1.49-1.38 (m, 2H).

[0309] The following compounds were synthesized by the same procedure asthe one of Example 208. TABLE 45 Ex. no. ¹H-NMR(400MHz)

CDCl₃8.49(dd, J=8, 1, 0.5H), 8.38(d, J=8, 0.5H), 7.67(dd, J=8, 1, 0.5H),7.48(d, J=8, 0.5H), 7.40-7.20(m, 2H), 7.10-6.92(m, 2H), 3.94(t, J=7,1H), 3.90(t, J=7, 1H), 2.37-2.29(m, 8H), 1.50-1.36(m, 2H) [a mixture ofE- and Z- (1:1)]

CDCl₃8.49(dd, J=8, 2, 0.5H), 8.37(d, J=8, 0.5H), 7.80(dd, J=8, 2, 0.5H),7.61(d, J=8, 0.5H), 7.40-7.22(m, 2H), 7.08-6.97(m, 2H), 4.34-4.26(m,2H), 4.00-3.90(m, 2H), 2.46-2.36(m, 2H), 2.34(s, 1.5H), 2.33(s, 1.5H),2.32(s, 1.5H), 2.31(s, 1.5H), 1.50-1.30(m, 5H) [a mixture of E- and Z-(1:1)]

CDCl₃8.46(d, J=8, 0.5H), 8.34(d, J=8, 0.5H), 7.74(dd, J=8, 1, 0.5H),7.56(d, J=8, 0.5H), 7.37-7.22(m, 2H), 7.06-6.90(m, 2H), 4.18(t, J=7,1H), 4.17(t, J=7, 1H), 4.05-3.90(m, 2H), 2.60-2.46(m, 2H), 2.38-2.22(m,6H), 1.86-1.75(m, 2H), 1.68-1.56(m, 2H), 1.01(t, J=7, 1.5H), 1.00(t,J=7, 1.5H) [a mixture of E- and Z- (1:1)]

CDCl₃8.59-8.51(m, 1H), 8.18(dd, J=8, 1, 0.5H), 8.10(d, J=8, 0.5H),7.77(dd, J=8, 2, 0.5H), 7.62-7.54(m, 1.5H), 7.37-7.00(m, 4.5H),6.95-6.84(m, 1.5H), 4.63(m, 2H), 4.00-3.88(m, 2H), 3.34-3.24(m, 2H),2.42(t, J=7, 2H), 2.32(s, 3H), 2.31(s, 1.5H), 2.30(s, 1.5H),1.52-1.40(m, 2H) [a mixture of E- and Z- (1:1)]

CDCl₃8.75(d, J=8, 0.5H), 8.62(d, J=8.0.5H), 7.89(dd, J=8, 1, 0.5H),7.72(d, J=8; 0.5H), 7.35-7.21(m, 2H), 7.05-7.00(m, 1H), 6.96(d, J=8,1H), 3.98-3.92(m, 2H), 2.66(s, 3H), 2.59(s, 3H), 2.41-2.35(m, 2H),2.31-2.28(m, 6H), 1.50-1.40(m, 2H) [a mixture of E- and Z- (1:1)]

CDCl₃8.49(dd, J=8.1, 0.5H), 8.39(d, J=8, 0.5H), 7.80(dd, J=8, 1, 0.5H),7.59(d, J=8, 0.5H), 7.46-7.24(m, 7H), 7.06-7.00(m, 1H), 6.96(d, J=8,1H), 5.31(s, 1H), 5.30(s, 1H), 3.98-3.89(m, 2H), 2.37(t, J=7, 2H),2.32-2.29(m, 6H), 1.45-1.38(m, 2H) [a mixture of E- and Z- (1:1)]

[0310] TABLE 46 Ex. no. ¹H-NMR(400MHz)

CDCl₃8.16(dd, J=8, 1, 0.5H), 8.02(d, J=8, 0.5H), 7.62(dd, J=8, 1, 0.5H)7.42(d, J=8, 0.5H), 7.40-7.18(m, 2H), 7.12-6.93(m, 2H), 4.60(s, 2H),3.90-3.70(m, 2H), 2.40-2.18(m, 8H), 1.65-1.53(m, 2H) [a mixture of E-and Z- (1:1)]

CDCl₃8.13(d, J=8, 0.5H), 8.01(d, J=8, 0.5H), 7.68(dd, J=8, 2, 0.5H),7.48(d, J=8, 0.5H), 7.38-7.17(m, 2H), 7.03(m, 0.5H), 6.96(d, J=8, 0.5H),6.88(d, J=8, 0.5H), 6.78(m, 0.5H), 4.37-4.28(m, 2H), 3.87-3.69(m, 2H),2.31(s, 1.5H), 2.30(s, 1.5H), 2.29(s, 1.5H), 2.28(s, 1.5H), 2.18-2.00(m,4H), 1.48-1.36(m, 2H) [a mixture of E- and Z- (1:1)]

CDCl₃8.15(d, J=8, 0.5H), 8.00(d, J=8, 0.5H), 7.59(dd, J=8, 1, 0.5H),7.40-7.03(m, 3.5H), 7.01(d, J=8, 0.5H), 6.96(d, J=8, 0.5H), 4.50(m, 1H),3.70-3.35(m, 2H), 2.32(s, 3H), 2.29(s, 1.5H), 2.28(s, 1.5H),2.08-1.90(m, 2H), 1.42-1.28(m, 2H), 1.27-1.15(m, 3H), [a mixture of E-and Z- (1:1)]

CDCl₃8.21(dd, J=8, 1, 0.5H), 8.07(d, J=8, 0.5H), 7.63(dd, J=8, 1, 0.5H),7.43(d, J=8, 0.5H), 7.40-6.92(m, 4H), 4.74-4.68(m, 1H), 4.10-3.94(m,1H), 3.76-3.62(m, 1H), 2.40-2.20(m, 8H), 2.23-1.82(m, 2H), 1.75-1.50(m,2H), 1.18-1.07(m, 3H) [a mixture of E- and Z- (1:1)]

DMSO-d6 7.83(d, J=8, 1H), 7.28-7.19(m, 2H), 6.98-6.87(m, 2H),3.93-3.78(m, 7H), 2.33(m, 2H), 2.24(s, 6H), 1.30(m, 2H)

CDCl₃8.49-8.43(m, 1.5H), 8.35(d, J=8, 0.5H), 7.72-7.64(m, 1.5H), 7.49(d,J=8, 0.5H), 7.48-7.14(m, 4H), 7.03-6.97(m, 1H), 6.94(d, J=8, 0.5H),6.90(d, J=8, 0.5H), 5.36(s, 1H), 5.33(s, 1H), 4.02-3.92(m, 2H), 2.50(t,J=8, 2H), 2.32(s, 1.5H), 2.30(s, 1.5H), 2.29(s, 1.5H), 2.27(s, 1.5H),1.65-1.55(m, 2H) [a mixture of E- and Z- (1:1)]

[0311] TABLE 47 Ex. no. ¹H-NMR(400MHz, CDCl₃)

CDCl₃8.29(dd, J=8, 2, 0.5H), 8.15(d, J=8, 0.5H), 7.69(dd, J=8, 2, 0.5H),7.50(d, J=8, 0.5H), 6.92-7.35(m, 4H), 4.22(m, 2H), 3.85(m, 2H),2.25-2.40(m, 8H), 1.95(m, 2H), 1.67(m, 2H), 1.58(m, 2H) [a mixture of E-and Z- (1:1)]

CDCl₃8.41(m, 0.5H), 8.30(m, 0.5H), 7.79(m, 0.5H), 7.60(t, J=8, 0.5H),6.90-7.40(m, 4H), 4.56(m, 2H), 4.06(m, 1H), 3.95(m, 1H), 3.02-3.06(m,3H), 2.98(s, 1.5H), 2.96(s, 1.5H), 2.88(m, 2H), 2.80(m, 1H), 2.42(t,J=7, 1H), 2.282.36(m, 6H), 1.70(m, 1H), 1.45(m, 1H), [a mixture of E-and Z- (1:1)]

CDCl₃8.50(dd, J=8, 2, 0.5H), 8.39(d, J=8, 0.5H), 7.80(dd, J=8, 2, 0.5H),7.61(d, J=8, 0.5H), 6.90-7.38(m, 4H), 4.48(m, 1H), 3.94(m, 2H), 2.44(m,2H), 2.33(s, 1.5H), 2.32(s, 1.5H), 2.31(s, 1.5H), 2.30(s, 1.5H), 1.47(m,2H), 1.38(s, 1.5H), 1.37(s, 1.5H), 1.36(s, 1.5H), 1.36(s, 1.5H) [amixture of E- and Z- (1:1)]

CDCl₃8.20(d, J=8, 0.5H), 7.99(d, J=8, 0.5H), 7.63(d, J=0.5H), 7.42(d,J=8, 0.5H), 6.88-7.36(m, 4H), 4.20(m, 2H), 3.82(m, 2H), 2.25-2.34(m,6H), 2.18(m, 2H), 1.42(m, 2H), 0.92-1.03(m, 4H) [a mixture of E- and Z-(1:1)]

CDCl₃8.35(d, J=8, 0.5H), 8.23(d, J=8, 0.5H),7.76(d, J=8, 0.5H), 7.57(d,J=8, 0.5H), 6.92-7.41(m, 4H), 6.54(brs, 0.5H), 6.46(brs, 0.5H),5.55(brs, 1H), 4.53(m, 2H), 3.95(m, 2H), 2.62(t, J=5, 2H), 2.28-2.40(m,8H), 1.44(m, 2H) [a mixture of E- and Z- (1:1)]

CDCl₃8.35(d, J=8, 0.5H), 8.23(d, J=8, 0.5H), 7.76(dd, J=8, 2, 0.5H),7.56(m, 05H), 6.90-7.44(m, 4H), 4.52(m, 2H), 4.01(m, 2H), 2.53-2.83(m,5H), 2.28-2.36(m, 8H), 1.40-1.70(m, 2H) [a mixture of E- and Z- (1:1)]

CDCl₃8.30(dd, J=8, 1, 0.5H), 8.18(d, J=8, 0.5H), 7.84(dd, J=8, 1, 0.5H),7.65(d, J=8, 0.5H), 6.98-7.45(m, 4H), 5.05(m, 1H), 4.00(m, 2H), 2.40(t,J=7, 2H), 2.32-2.37(m, 6H), 1.77(d, J=7, 1.5H), 1.76(d, J=7, 1.5H),1.46(m, 2H) [a mixture of E- and Z- (1:1)]

[0312] TABLE 48 Ex. no. ¹H-NMR(400MHz, CDCl₃)

CDCl₃8.35(d, J=8, 0.5H), 8.21(d, J=8, 0.5H), 7.75(d, J=8, 0.5H), 7.55(d,J=8, 0.5H), 7.26-7.40(m, 2H), 6.92-7.10(m, 2H), 4.48(m, 2H), 4.06(m,2H), 2.65(m, 2H), 2.59(m, 2H), 2.28-2.38(m, 6H) [a mixture of E- and Z-(1:1)]

Example 229

[0313](E,Z)-3,4-Dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-methylEther

[0314] A mixture of 200 mg of(E,Z)-3,4-dimethyl-10-(3-aminopropyl)-9-acridoneoxime-O-methyl etherwith 140 mg of benzaldehyde was stirred under reflux in 50 ml ofethanol. After cooling the mixture to room temperature, 200 mg of sodiumborohydride was added thereto followed by stirring at room temperaturefor 10 min. After adding water, the reaction mixture was extracted withethyl acetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto give 180 mg of the title compound as a mixture of the E- andZ-enantiomers (1:1).

[0315]¹H-NMR,(400 MHz, CDCl₃) δ

[0316] 8.43 (dd, J=8, 2, 0.5H), 8.33 (d, J=8, 0.5H), 7.81 (dd, J=8, 2,0.5H), 7.62 (d, J 8, 0.5H), 7.38-6.96 (m, 9H), 4.06 (s, 1.5H), 4.05 (s,1.5H), 4.02-3.93 (m, 2H), 3.50 (s, 2H), 2.38-2.29 (m, 8H), 1.55-1.45 (m,2H).

[0317] The following compounds were synthesized by the same procedure asthe one of Example 229. TABLE 49 Ex. no. ¹H-NMR(400MHz) δ

CDCl₃8.58(d, J=8, 0.5H), 8.49(d, J=8, 0.5H), 7.74(d, J=8, 0.5H), 7.56(d,J=8, 0.5H), 7.40-6.88(m, 9H), 4.02-3.88(m, 2H), 3.50(s, 2H),2.45-2.18(m, 8H), 1.60-1.40(m, 2H) [a mixture of E- of Z- (1:1)]

CDCl₃8.49(dd, J=8, 1, 0.5H), 8.38(d, J=8, 0.5H); 7.81(dd, J=8, 1, 0.5H),7.62(d, J=8, 0.5H), 7.40-6.96(m, 9H), 4.34-4.25(m, 2H), 4.02-3.93(m, 2H)3.50(s, 2H), 2.38-2.29(m, 2H), 2.33(s, 1.5H), 2.32(s, 1.5H), 2.31(s,1.5H), 2.30(s, 1.5H), 1.60-1.42(m, 2H), 1.40(t, J=8, 3H) [a mixture ofE- and Z- (1:1)]

CDCl₃8.48(dd, J=8, 2, 0.5H), 8.38(d, J=8, 0.5H), 7.80(dd, J=8, 2, 0.5H),7.61(d, J=8, 0.5H), 7.40-6.95(m, 9H), 4.22(t, J=7, 1H), 4.20(t, J=7,1H), 4.02-3.92(m, 2H), 3.50(s, 1H), 3.49(s, 1H), 2.40-2.28(m, 2H),2.33(s, 1.5H), 2.32(s, 1.5H), 2.31(s, 1.5H), 2.30(s, 1.5H), 1.87-1.74(m,2H), 1.62-1.42(m, 2H), 1.02(t, J=8, 3H) [a mixture of E- and Z- (1:1)]

CDCl₃8.52(dd, J=8, 1, 0.5H), 8.41(d, J=8, 0.5H), 7.81(dd, J=8, 1, 0.5H),7.62(d, J=8, 0.5H), 7.48-7.00(m, 13H), 6.97(d, J=8, 1H), 5.32(s, 1H),5.31(s, 1H), 4.01-3.92(m, 2H), 3.48(s, 2H), 2.36-2.29(m, 8H),1.52-1.48(m, 2H)

[0318] TABLE 50 Ex. no. ¹H-NMR (400 MHz₃) δ 234

CDCl₃8.21(dd, J=8, 1, 0.5H), 8.02(d, J= 8, 0.5H), 7.61(dd, J=8, 1,(0.5H), 7.43(d, J=8, 0.5H), 7.38-6.92(m, 9H), 4.66(s, 1H), 4.65(s, 1H),3.84-3.66(m, 2H), 3.49(s, 1H), 3.46(s, 1H), 2.28(s, 3H), 2.27(s, 3H),2.20-2.07(m, 2H), 1.85-1.57(m, 2H) [a mixture of E- and Z- (1:1)] 235

CDCl₃8.22(d, J=8, 0.5H), 8.05(d, J=8, 0.5H), 7.61(dd, J=8, 1, 0.5H),7.43(d, J=8, 0.5H), 7.30-6.83(m, 9H), 4.60-4.48(m, 2H), 3.70-3.52(m,2H), 3.44(s, 1H), 3.37(s, 1H), 2.40-2.30(m, 2H), 2.29(s, 1.5H), 2.26(s,1.5H), 2.25(s, 1.5H), 2.19(s, 1.5H), 2.12-1.98(m, 2H), 1.37-1.20(m, 2H)[a mixture of E- and Z- (1:1)] 236

CDCl₃8.23(dd, J=8, 1, 0.5H), 8.09(d, J=8, 0.5H), 7.57(dd, J=8, 1, 0.5H),7.41(d, J=8, 0.5H), 7.36-7.02(m, 8H), 6.97(d, J=8, 0.5H), 6.91(d, J=8,0.5H), 4.85(q, J=7, 1H), 4.00-3.88(m, 1H), 3.80-3.60(m, 3H),2.32-2.10(m, 8H), 1.80-1.62(m, 2H), 1.58(t, J=7, 3H) [a mixture of E-and Z- (1:1)] 237

CDCl₃8.25(d, J=8, 0.5H), 8.09(d, J=8, 0.5H), 7.61(d, J=8, 0.5H), 7.44(d,J=8, 0.5H), 7.35-6.90(m, 9H), 4.75-4.67(m, 1H), 3.94-3.83(m, 1H),3.72-3.44(m, 3H), 2.28(s, 3H), 2.27(s, 3H), 2.26-1.85(m, 4H),1.80-1.52(m, 2H), 1.14(t, J=7, 3H) [a mixture of E- and Z- (1:1)] 238

CDCl₃8.34(dd, J=8, 1, 0.5H), 8.23(d, J=8, 0.5H), 7.72(dd, J=8, 1, 0.5H),7.54(d, J=8, 0.5H), 7.33-6.90(m, 4H), 6.77(s, 2H), 3.97(s, 1.5H),3.96(s, 1.5H), 3.95-3.87(m, 2H), 3.45(s, 2H), 2.26-2.18(m, 6H),2.22-2.14(m, 2H), 1.48-1.40(m, 2H) [a mixture of E- and Z- (1:1)] 239

CDCl₃8.01(d, J=8, 1H), 7.30(t, J=8.1H), 7.23-7.06(m, 7H), 7.00(d, J=8,1H), 4.02(s, 3H), 3.97(m, 2H), 3.91(s, 2H), 3.50(s, 2H), 2.31(s, 3H),2.30(s, 3H), 2.32-2.29(m, 2H), 1.58-1.49(m, 2H) 240

CDCl₃8.60-8.48(m, 1H), 8.46(d, J=8, 0.5H), 7.77(m, J=8, 0.5H),7.64-6.88(m, 13H), 5.44(s, 1H), 5.43(s, 1H), 4.06-3.88(m, 2H), 3.50(s,1H), 3.48(s, 1H), 2.42-2.22(m, 8H), 1.70-1.44(m, 2H) [a mixture of E-and Z- (1:1)]

[0319] TABLE 51 Ex. no. ¹H-NMR (400 MHz) δ 241

CDCl₃8.57-8.53(m, 1H), 8.20(dd, J=8, 1, 0.5H), 8.11(d, J=8, 0.5H),7.78(dd, J=8, 1, 0.5H), 7.60(d, J=8, 0.5H), 7.59-7.53(m, 1H),7.37-7.02(m, 9.5H), 7.00-6.84(m, 1.5H), 4.66-4.58(m, 2H), 4.02-3.90(m,2H), 3.52(s, 1H), 3.49(s, 1H), 3.31-3.23(m, 2H), 2.39-2.23(m, 8H),1.58-1.47(m, 2H) [a mixture of E- and Z- (1:1)] 242

CDCl₃8.40(dd, J=8, 2, 0.5H), 8.27(d, J=8, 0.5H), 8.05(dd, J=8, 2, 0.5H),7.76(dd, J=8, 2, 0.5H), 7.57(d, J=8, 0.5H), 6.94-7.40(m, 8.5H), 4.28(m,2H), 3.95(m, 2H), 3.75(s, 1H), 3.73(s, 1H), 2.47(m, 2H), 2.26-2.35(m,8H), 1.99(m, 2H), 1.76(m, 2H) [a mixture of E- and Z- (1:1)] 243

CDCl₃8.52(dd, J=8, 2, 0.5H), 8.40(d, J=8, 0.5H), 7.81(dd, J=8, 2, 0.5H),7.63(d, J=8, 0.5H), 6.94-7.36(m, 9H), 4.49(m, 1H), 3.96(m, 2H), 3.49(s,2H), 2.34(m, 2H), 2.32(s, 1.5H), 2.32(s, 1.5H), 2.31(s, 1.5H), 2.30(s,1.5H), 1.51(m, 2H), 1.38(s, 1.5H), 1.37(s, 1.5H), 1.36(s, 1.5H),1.36(1.5H) [a mixture of E- and Z- (1:1)] 244

CDCl₃8.42(dd, J=8, 2, 0.5H), 8.32(d, J=8, 0.5H), 7.80(dd, J=8, 2, 0.5H),7.61(d, J=8, 0.5H), 6.94-7.40(m, 9H), 4.56(q, J=7, 2H), 3.98(m, 2H),3.50(s, 2H), 3.01(s, 1.5H), 3.00(s, 1.5H), 2.96(s, 1.5H), 2.96(s, 1.5H),2.86(t, J=7, 2H), 2.28-2.38(m, 8H), 1.49(m, 2H) [a mixture of E- and Z-(1:1)] 245

DMSO-d6 8.42(s, 1H), 8.31(m, 0.5H), 8.18(m, 0.5H), 8.06(m, 0.5H),7.86(m, 0.5H), 6.90-7.83(m, 7H), 4.35(m, 2H), 3.97(m, 2H), 3.57(s, 2H),2.57(m, 2H), 2.28(s, 3H), 2.27(s, 3H), 2.21(m, 2H), 1.38(m, 2H) [amixture of E- and Z- (1:1)] 246

CDCl₃8.77(d, J=8, 0.5H), 8.64(d, J=8, 0.5H), 7.93(dd, J=8, 1, 0.5H),7.76(d, J=8, 0.5H), 7.34-7.00(m, 8H), 6.97(d, J=8, 1H), 4.00-3.94(m,2H), 3.53(s, 1H), 3.52(s, 1H), 2.67(s, 3H), 2.60(s, 3H), 2.40-2.34(m,2H), 2.31-2.28(m, 6H), 1.58-1.48(m, 2H) [a mixture of E- and Z- (1:1)]

[0320] TABLE 52 Ex. no. ¹H-NMR (400 MHz) δ 247

DMSO-d6 8.36(d, J=8, 0.5H), 8.26(d, J=8, 0.5H), 7.71(d, J=8, 0.5H),6.70-7.56(m, 8.5H), 4.36(m, 2H), 3.96(m, 2H), 3.83(s, 2H),2.60-2.76(4H), 2.25-2.37(m, 6H), 1.51(m, 2H) [a mixture of E- and Z-(1:1)] 248

CDCl₃8.26(d, J=8, 0.5H), 8.09(d, J=, 0.5H), 6.92-8.04(m, 10H), 4.34(m,2H), 3.68-3.80(m, 4H), 2.24-2.36(m, 8H), 1.63(m, 2H), 1.16-1.26(m, 6H)[a mixture of E- and Z- (1:1)] 249

DMSO-d6 8.33(d, J=8, 0.5H), 8.21(d, J=0.5H), 7.69(d, J=8, 0.5H),7.34-7.54(m, 2.5H), 6.9-7.16(m, 6H), 4.36(m, 2H), 3.99(m, 2H), 3.43(s,1H), 3.42(s, 1H), 2.63(m, 2H), 2.21-2.36(m, 8H), 2.15(s, 3H), 1.37(m,2H) [a mixture of E- and Z- (1:1)] 250

DMSO-d6 8.33(d, J=8, 0.5H), 8.23(d, J=8, 0.5H), 8.07(m, 0.5H), 7.88(m,0.5H), 7.69(d, J=8, 0.5H), 6.86-7.53(m, 7.5H), 4.36(m, 2H), 4.01(m, 2H),3.48(s, 1H), 3.47(s, 1H), 2.68(m, 2H), 2.14-2.34(m, 8H) 1.34(m, 2H) [amixture of E- and Z- (1:1)] 251

CDCl₃8.35(dd, J=8, 2, 0.5H), 8.23(d, J=8, 0.5H), 7.76(dd, J=8, 2, 0.5H),7.57(d, J=8, 0.5H), 6.96-7.41(m, 9H), 6.23(brs, 1H), 5.55(brs, 1H),4.52(m, 2H), 3.94(m, 2H), 3.55(s, 1H), 3.54(s, 1H), 2.64(m, 2H),2.26-2.40(m, 8H), 1.51(m, 2H) [a mixture of E- and Z- (1:1)] 252

CDCl₃8.34(dd, J=8, 2, 0.5H), 8.23(d, J=8, 0.5H), 7.77(dd, J=8, 2, 0.5H),7.58(dd, J=8, 0.5H), 6.94-7.42(m, 9H), 6.33(brs, 0.5H), 6.28(brs, 0.5H),4.51(m, 2H), 3.99(m, 2H), 3.52(s, 2H), 2.65(d, J=5, 1.5H), 2.60(d, J=5,1.5H), 2.55-2.63(m, 2H), 2.29-2.38(m, 8H), 1.52(m, 2H) [a mixture of E-and Z- (1:1)] 253

CDCl₃8.32(dd, J=8, 1, 0.5H), 8.20(d, 0.5H), 8.60(d, J=8, 0.5H), 7.67(d,J=8, 0.5H), 6.97-7.42(m, 9H), 5.03(m, 1H), 4.01(m, 2H), 3.51(s, 2H),2.30-2.38(m, 8H), 1.76(d, J=7, 1.5H), 1.75(d, J=7, 1.5H), 1.53(m, 2H) [amixture of E- and Z- (1:1)]

[0321] TABLE 53 Ex. no. ¹H-NMR (400 MHz, CDCl₃) 254

CDCl₃8.36(dd, J=8, 2, 0.5H), 8.22(d, J=8, 0.5H), 7.77(dd, J=8, 2, 0.5H),7.58(d, J=8, 0.5H), 6.95-7.38(m, 9H), 4.55(m, 2H), 3.84(m, 2H), 3.50(s,2H), 2.63(m, 2H), 2.31(s, 6H), 2.17(m, 2H), 2.01(s, 1.5H), 2.00(s,1.5H), 1.56(m, 2H) [a mixture of E- and Z- (1:1)] 255

CDCl₃8.49(dd, J=8, 2, 0.5H), 8.39(d, J=8, 0.5H), 7.80(dd, J=8, 2, 0.5H),7.62(d, J=8, 0.5H), 6.95-7.38(m, 9H), 4.31(m, 2H), 3.91(m, 2H), 3.44(m,1H), 2.28-2.32(m, 6H), 2.08-2.26(m, 2H), 1.38-1.46(m, 5H), 1.14(m, 3H)[a mixture of E- and Z- (1:1)] 256

DMSO-d6 8.39(d, J=8, 0.5H), 8.29(d, J=8, 0.5H), 7.96(d, J=8, 0.5H),7.54(d, J=8, 0.5H), 7.54(d, J=8, 0.5H), 6.92-7.41(m, 8.5H), 4.39(m, 2H),4.02(m, 2H), 3.41(s, 1H), 3.40(s, 1H), 2.69(t, J=7, 2H), 2.46(m, 2H),2.31(s, 3H), 2.30(s, 3H) [a mixture of E- and Z- (1:1)]

[0322] The following compounds were obtained by the same procedures asthose of Production Examples 15, 2 and Example 1. TABLE 54 Ex. no.¹H-NMR (400 MHz) δ 257

CDCl₃7.54-7.50(m, 1H), 7.33-7.28(m, 1H), 7.21-7.07(m, 3H), 7.04-6.99(m,1H), 3.58-3.56(m, 3H), 3.56-3.38(m, 2H), 3.22-3.15(m, 1H), 2.77-2.72(m,1H), 2.38(s, 3H), 2.26(s, 3H), 1.88-1.60(m, 2H) 258

CDCl₃7.82-7.78(m, 1H), 7.40-7.34(m, 1H), 7.19(dd, J=8, 1, 1H), 7.07(t,d, J=8, 1, 1H), 7.00-6.93(m, 2H), 3.90-3.82(m, 1H), 3.54(s, 3H),3.23-3.10(m, 1H), 2.28(s, 3H), 2.23(s, 3H), 1.90-1.75(m, 2H),1.70-1.55(m, 2H)

[0323] The following compounds were obtained by the same procedures asthose of Production Examples 15, 2, Examples 1 and 22. TABLE 55 Ex. no.¹H-NMR (400 MHz) δ 259

CDCl₃7.54(d, J=8, 1H), 7.33-7.06(m, 9H), 7.02(d, J=8, 1H), 3.71(s, 2H),3.56(s, 3H), 3.55-3.35(m, 2H), 2.66-2.62(m, 2H), 2.35(s, 3H), 2.26(s,3H), 1.71-1.61(m, 2H) 260

CDCl₃7.80(dd, J=8, 1, 1H), 7.39-7.19(m, 6H), 7.17(dd, J=8, 1, 1H),7.08(t d, J=8, 1, 1H), 6.98(d, J=8, 1H), 6.93(d, J=8, 1H), 3.91-3.83(m,1H), 3.70(s, 2H), 3.48(s, 3H), 3.45‥3.40(m, 1H), 2.68-2.60(m, 2H),2.26(s, 3H), 2.22(s, 1H), 1.74-1.64(m, 2H)

[0324] The following compounds were obtained by the same procedures asthose of Examples 22 and 164. TABLE 56 Ex. no. ¹H-NMR (400 MHz) 261

CDCl₃7.64(m, 1H), 7.48-7.40(m, 3H), 7.30-7.18(m, 4H), 7.05(d, J=8, 1H),6.99(dd, J=8, 2, 1H), 4.48(m, 1H), 4.13(d, J=14, 1H), 4.00(m, 1H),3.89(d, J=14, 1H), 3.77(d, J=16, 1H), 3.71(d, J=16, 1H), 3.59(s, 3H),2.72(m, 2H), 2.33(s, 3H), 2.32(s, 3H), 2.05-1.82(m, 2H) 262

DMSO-d6 7.65(d, J=8, 1H), 7.54(d, J=8, 1H), 7.48(t, J=8, 1H),7.28-7.18(m, 5H), 7.14(d, J=8, 1H), 7.05(d, J=8, 1H), 4.50(m, 1H),4.05(d, J=14, 1H), 3.95(m, 1H), 3.85(d, J=14, 1H), 3.55(s, 2H),2.42-2.39(m, 2H), 2.32(s, 3H), 2.30(s, 3H), 1.63-1.58(m, 2H)

1. A nitrogen-containing tricyclic compound represented by the followingformula (I), a hydrate thereof or a pharmacologically acceptable saltthereof:

wherein R¹, R², R3, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different fromeach other and each represents hydrogen, hydroxy, cyano, nitro,optionally substituted carbamoyl, halogeno, optionally halogenated loweralkyl, optionally substituted cycloalkyl, optionally halogenated loweralkoxy, acyl, optionally protected carboxyl, optionally substitutedaryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylatedalkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionallyhalogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protectedcarboxyalkenyl, optionally substituted arylalkenyl, optionallysubstituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionallysubstituted carbamoylalkenyl, optionally halogenated alkynyl,hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl,optionally substituted arylalkynyl, optionally substitutedheteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substitutedcarbamoyalkynyl, hydroxyalkoxy, alkoxyalkoxy, optionally protectedcarboxyalkoxy, optionally substituted arylalkoxy, optionally substitutedheteroarylalkoxy, —A—NR⁹R¹⁰, wherein A represents optionally substitutedalkylene, optionally substituted alkenylene, optionally substitutedalkynylene or a single bond; and R⁹ and R¹⁰ are the same or differentfrom each other and each represents hydrogen, optionally halogenatedlower alkyl, optionally substituted aryl or acyl, or R⁹ and R¹⁰ may formtogether with the nitrogen atom to which they are bonded a ringoptionally having additional nitrogen, oxygen or sulfur, or

wherein B represents optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkynylene or a singlebond; R¹ represents optionally halogenated lower alkyl or aminooptionally substituted by lower alkyl; and x represents an integer offrom 0 to 2; provided that two of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸adjacent to each other may form together with the carbon atom to whichthey are bonded a ring optionally containing oxygen, sulfur or nitrogenand optionally substituted; Z represents

wherein R¹⁵, R¹⁶ and R¹⁷ are the same or different from each other andeach represents hydrogen, optionally substituted carbamoyl, optionallyhalogenated lower alkyl, optionally substituted cycloalkyl, acyl,optionally halogenated lower alkylsulfonyl, optionally substitutedarylsulfonyl, optionally protected carboxyl, optionally substitutedaryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylatedalkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionallysubstituted arylakyl, optionally substituted heteroarylalkyl,cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionallyhalogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protectedcarboxyalkenyl, optionally substituted arylalkenyl, optionallysubstituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionallysubstituted carbamoyalkenyl, optionally halogenated alkynyl,hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl,optionally substituted arylalkynyl, optionally substitutedheteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substitutedcarbamoylalkynyl, —W—NR¹⁸R¹⁹, wherein W represents optionally branchedalkylene, optionally branched alkenylene, optionally branched alkynyleneor a single bond; R¹⁸ and R¹⁹ are the same or different from each otherand each represents hydrogen, optionally halogenated lower alkyl oracyl, or R¹⁸ and R¹⁹ may form together with the nitrogen atom to whichthey are bonded a ring optionally containing additional nitrogen, oxygenor sulfur; D represents optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkynylene or

wherein m and 1 are each an integer of from 0 to 6; the ring A means anoptionally substituted hydrocarbon ring or an optionally substitutedheterocycle; and Q represents optionally substituted carbamoyl, acyl,acylalkyl, optionally protected carboxyl, optionally substitutedheteroaryl, or —NR²⁰R²¹, wherein R²⁰ and R²¹ are the same or differentfrom each other and each represents hydrogen, optionally halogenatedlower alkyl, optionally halogenated lower alkoxy, hydroxylated alkyl,alkoxyalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted aryloxy, optionally substitutedarylalkoxy, optionally substituted heteroaryloxy, optionally substitutedheteroarylalkoxy, optionally protected carboxyalkyl, acyl, optionallysubstituted acylalkyl, optionally substituted acylamino, optionallysubstituted acylaminoalkyl, optionally substituted carbamoylalkyl,optionally substituted aminoalkyl, cyanoalkyl, acylalkyl, cycloalkyl,cycloalkylalkyl or amindino optionally substituted by lower alkyl, orR²⁰ and R²¹ may form together with the nitrogen atom to which they arebonded an optionally substituted 3- to 8-membered ring which may have,as its ring-member other than carbon, at least one member selected fromthe group consisting of nitrogen, sulfur, oxygen and —NR²², wherein R²²represents hydrogen, optionally halogenated lower alkyl, acyl,optionally substituted acylalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted arylalkyl,optionally substituted heteroarylalkyl or —S(O)_(s)—(Y)_(u)—R²³, whereinR²³ represents hydrogen, optionally halogenated lower alkyl oroptionally substituted aryl; Y represents methylene; s is an integer offrom 0 to 2; and u is 0 or 1, provided that the following compound isexcluded: the compound where R⁵ and R⁶ are both hydrogen atoms.
 2. Anitrogen-containing tricyclic compound as set forth in claim 1, ahydrate thereof or a pharmacologically acceptable salt thereof, whereinneither R⁵ nor R⁶ is hydrogen.
 3. The nitrogen-containing tricycliccompound as set forth in any of claims 1 or 2, a hydrate thereof or apharmacologically acceptable salt thereof, wherein Z is


4. The nitrogen-containing tricyclic compound as set forth in any ofclaims 1 or 2, a hydrate thereof or a pharmacologically acceptable saltthereof, wherein Z is


5. The nitrogen-containing tricyclic compound as set forth in claim 1, ahydrate thereof or a pharmacologically acceptable salt thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different from eachother and each represents hydrogen, hydroxy, cyano, optionallysubstituted carbamoyl, halogeno, optionally halogenated lower alkyl,optionally substituted cycloalkyl, optionally halogenated lower alkoxy,acyl, optionally protected carboxyl, optionally substituted aryl,optionally substituted heteroaryl, hydroxylated alkyl, alkoxyalkyl,optionally protected carboxyalkyl, or —A—NR⁹R¹⁰ (wherein A representsoptionally substituted alkylene or a single bond; and R⁹ and R¹⁰ are thesame or different from each other and each represents hydrogen,optionally halogenated lower alkyl, or acyl).
 6. The nitrogen-containingtricyclic compound as set forth in claim 1, a hydrate thereof or apharmacologically acceptable salt thereof, wherein Q represents—NR²⁰R²¹, wherein R and R are the same or different from each other andeach represents hydrogen, lower alkyl, lower alkoxy, hydroxylated alkyl,alkoxyalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkoxy, optionallyprotected carboxyalkyl, acyl, optionally substituted acylamino,optionally substituted acylaminoalkyl, optionally substitutedaminoalkyl, cyanoalkyl, acylalkyl, cycloalkyl or cycloalkylalkyl, or R²⁰and R²¹ may form together with the nitrogen atom to which they arebonded an optionally substituted 3- to 8-membered ring which may have,as its ring-member other than carbon, furthermore, nitrogen, sulfur,oxygen or —NR²², wherein R²² represents hydrogen, optionally halogenatedlower alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl or —S(O)_(s)—(Y)^(u)—R²³, wherein R²³ representshydrogen, optionally halogenated lower alkyl or optionally substitutedaryl; Y represents methylene; s is 0 or an integer of 1 or 2; and u is 0or 1, or may be condensed with an optionally substituted benzene ring.7. The nitrogen-containing tricyclic compound as set forth in claim 1, ahydrate thereof or a pharmacologically acceptable salt thereof, whereinQ is —NR²OR²¹, wherein: i) R²⁰ and R²¹ are the same or different fromeach other and each represents hydrogen, lower alkyl, hydroxylatedalkyl, alkoxyalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally protected carboxyalkyl, cyanoalkyl orcycloalkylalkyl; ii) R²⁰ and R²¹ may form together with the nitrogenatom to which they are bonded an optionally substituted 5- to 6-memberedring which may have, as its ring-member other than carbon, at least onemember selected from the group consisting of sulfur, oxygen or —NR²²,wherein R²² represents hydrogen, optionally halogenated lower alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substituted heteroarylalkylor —S(O)_(s)—(Y)_(u)—R²³, wherein R²³ represents hydrogen, lower alkylor optionally substituted aryl; Y represents methylene; s is an integerof from 0 or 2; and u is 0 or 1; or iii) the ring formed by R²⁰, R²¹ andthe nitrogen atom to which they are bonded is tetrahydroquinoline,tetrahydroisoquinoline, indoline or isoindoline.
 8. Thenitrogen-containing tricyclic compound as set forth in claim 1, ahydrate thereof or a pharmacologically acceptable salt thereof, whereinR⁵ and R⁶ are each lower alkyl.
 9. The nitrogen-containing tricycliccompound as set forth in claim 1, a hydrate thereof or apharmacologically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁷and R⁸ are each hydrogen; R⁵ and R⁶ are each lower alkyl; and Z is


10. The nitrogen-containing tricyclic compound as set forth in claim 1,a hydrate thereof or a pharmacologically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁷ and R⁸ are each hydrogen; R⁵ and R⁶ are eachlower alkyl; and Z is


11. The nitrogen-containing tricyclic compound as set forth in claim 1,a hydrate thereof or a pharmacologically acceptable salt thereof,wherein R⁵ and R⁶ are the same or different from each other and eachrepresents methyl or ethyl.
 12. The nitrogen-containing tricycliccompound as set forth in claim 1, a hydrate thereof or apharmacologically acceptable salt thereof, wherein R⁵ and R⁶ are eachmethyl.
 13. The nitrogen-containing tricyclic compound as set forth inclaim 1, a hydrate thereof or a pharmacologically acceptable saltthereof, wherein R¹, R², R³, R⁴, R⁷ and R⁸ are the same or differentfrom each other and each represents hydrogen, cyano, optionallysubstituted carbamoyl, halogeno, optionally halogenated lower alkyl,optionally substituted cycloalkyl, optionally halogenated lower alkoxy,acyl, optionally protected carboxyl, optionally substituted aryl,optionally substituted heteroaryl, hydroxyalkyl, alkoxyalkyl, optionallyprotected carboxyalkyl, or —A—NR⁹R¹⁰, wherein A represents optionallysubstituted alkylene, or a single bond; and R⁹ and R¹⁰ are the same ordifferent from each other and each represents hydrogen, optionallyhalogenated lower alkyl or acyl; R⁵ and R6 are each methyl; and z is


14. The nitrogen-containing tricyclic compound as set forth in claim 1,a hydrate thereof or a pharmacologically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁷ and R⁸ are the same or different from eachother and each represents hydrogen, cyano, optionally substitutedcarbamoyl, halogeno, optionally halogenated lower alkyl, optionallysubstituted cycloalkyl, optionally halogenated lower alkoxy, acyl,optionally protected carboxyl, optionally substituted aryl, optionallysubstituted heteroaryl, hydroxyalkyl, alkoxyalkyl, optionally protectedcarboxyalkyl, or —A—NR⁹R¹⁰, wherein A represents optionally substitutedalkylene, or a single bond; and R⁹ and R¹⁰ are the same or differentfrom each other and each represents hydrogen, optionally halogenatedlower alkyl or acyl; R⁵ and R⁶ are each methyl; and z is


15. A pharmaceutical composition containing a pharmacologicallyeffective amount of the nitrogen-containing tricyclic compound as setforth in claim 1, a hydrate thereof or a pharmacologically acceptablesalt thereof together with pharmacologically acceptable carriers. 16.The composition as set forth in claim 15, which is a tyrosine kinaseinhibitor, a preventive or a remedy for diseases against which thetyrosine kinase inhibitory effect is efficacious, an antiallergic agent,a preventive or a remedy for diseases against which the antiallergiceffect is efficacious, or a preventive or a remedy for asthma, allergicrhinitis, atopic dermatitis, hay fever, allergic conjunctivitis and foodallergy.
 17. A method for preventing or treating diseases against whichthe effect of inhibiting the binding of the IgE receptor γ chain to atyrosine kinase of 72 kDa is efficacious by administering apharmacologically effective amount of the nitrogen-containing tricycliccompound as set forth in claim 1, a hydrate thereof or apharmacologically acceptable salt thereof to a patient with diseasesagainst which the effect of inhibiting the binding of the IgE receptor γchain to a tyrosine kinase of 72 kDa is efficacious.
 18. The method asset forth in claim 17 for preventing or treating diseases caused by theliberation of chemical mediators such as serotonin, histamine andleukotrienes.
 19. The method as set forth in claim 17 for preventing ortreating allergic diseases such as asthma, allergic rhinitis, atopicdermatitis, urticaria, hay fever, gastrointestinal allergy or foodallergy.
 20. The method as set forth in claim 17 which comprisesadministering from about 0.03 to 1,000 mg/day of the active ingredientto an adult patient.
 21. The method as set forth in claim 17 whichcomprises administering from 1 μg/kg to 3,000 μg/kg of the activeingredient as an injection to an adult patient.